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1
Fleming, James A., Leticia R. Vega, and Frank Solomon. "Function of Tubulin Binding Proteins in Vivo." Genetics 156, no. 1 (September 1, 2000): 69–80. http://dx.doi.org/10.1093/genetics/156.1.69.
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Abstract Overexpression of the β-tubulin binding protein Rbl2p/cofactor A is lethal in yeast cells expressing a mutant α-tubulin, tub1-724, that produces unstable heterodimer. Here we use RBL2 overexpression to identify mutations in other genes that affect formation or stability of heterodimer. This approach identifies four genes—CIN1, CIN2, CIN4, and PAC2—as affecting heterodimer formation in vivo. The vertebrate homologues of two of these gene products—Cin1p/cofactor D and Pac2p/cofactor E—can catalyze exchange of tubulin polypeptides into preexisting heterodimer in vitro. Previous work suggests that both Cin2p or Cin4p act in concert with Cin1p in yeast, but no role for vertebrate homologues of either has been reported in the in vitro reaction. Results presented here demonstrate that these proteins can promote heterodimer formation in vivo. RBL2 overexpression in cin1 and pac2 mutant cells causes microtubule disassembly and enhanced formation of Rbl2p-β-tubulin complex, as it does in the α-tubulin mutant that produces weakened heterodimer. Significantly, excess Cin1p/cofactor D suppresses the conditional phenotypes of that mutant α-tubulin. Although none of the four genes is essential for viability under normal conditions, they become essential under conditions where the levels of dissociated tubulin polypeptides increase. Therefore, these proteins may provide a salvage pathway for dissociated tubulin heterodimers and so rescue cells from the deleterious effects of free β-tubulin.
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Masocha, Willias. "Targeting the Endocannabinoid System for Prevention or Treatment of Chemotherapy-Induced Neuropathic Pain: Studies in Animal Models." Pain Research and Management 2018 (July 25, 2018): 1–9. http://dx.doi.org/10.1155/2018/5234943.
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There is a scarcity of drugs to either prevent or properly manage chemotherapy-induced neuropathic pain (CINP). Cannabis or cannabinoids have been reported to improve pain measures in patients with neuropathic pain. For this review, a search was done in PubMed for papers that examined the expression of and/or evaluated the use of cannabinoids or drugs that prevent or treat established CINP in a CB receptor-dependent manner in animal models. Twenty-eight articles that fulfilled the inclusion and exclusion criteria established were analysed. Studies suggest there is a specific deficiency of endocannabinoids in the periphery during CINP. Inhibitors of FAAH and MGL, enzymes that degrade the endocannabinoids, CB receptor agonists, desipramine, and coadministered indomethacin plus minocycline were found to either prevent the development and/or attenuate established CINP in a CB receptor-dependent manner. The studies analysed suggest that targeting the endocannabinoid system for prevention and treatment of CINP is a plausible therapeutic option. Almost 90% of the studies on animal models of CINP analysed utilised male rodents. Taking into consideration clinical and experimental findings that show gender differences in the mechanisms involved in pain including CINP and in response to analgesics, it is imperative that future studies on CINP utilise more female models.
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Hoyt, M. Andrew, Jennifer P. Macke, B. Tibor Roberts, and John R. Geiser. "Saccharomyces cerevisiae PAC2 Functions With CIN1, 2 and 4 in a Pathway Leading to Normal Microtubule Stability." Genetics 146, no. 3 (July 1, 1997): 849–57. http://dx.doi.org/10.1093/genetics/146.3.849.
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The products of the Saccharomyces cerevisiae CIN1, CIN2 and CIN4 genes participate in a nonessential pathway required for normal microtubule function. In this article, we demonstrate that the product of PAC2 also functions in this pathway. PAC2 deletion mutants displayed phenotypes and genetic interactions similar to those caused by cin1Δ, cin2Δ and cin4Δ. These include cold-sensitive microtubule structures and sensitivity to the microtubule depolymerizing agent benomyl. Involvement in a common functional pathway is indicated by the observation that all double mutant combinations are viable and no more affected than any single mutant. In addition, extra copies of CIN1 were found to suppress the benomyl sensitivity of pac2Δ, cin2Δ and cin4Δ, but not that caused by other mutations that affect microtubule function. Cin1p and Pac2p were found to be related in sequence to mammalian proteins that aid in the folding of β-tubulin into an assembly-competent state. Alleles of CIN1 were identified that could suppress the benomyl sensitivity of cin4-4 in a highly specific fashion. Our findings suggest that the guanine nucleotide-binding Cin4p interacts with Cin1p and regulates its tubulin folding activity.
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Son, Dang Bao, Woosik Choi, Mingu Kim, Eun Jin Go, Dabeen Jeong, Chul-Kyu Park, Yong Ho Kim, Hanki Lee, and Joo-Won Suh. "Decursin Alleviates Mechanical Allodynia in a Paclitaxel-Induced Neuropathic Pain Mouse Model." Cells 10, no. 3 (March 4, 2021): 547. http://dx.doi.org/10.3390/cells10030547.
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Chemotherapy-induced neuropathic pain (CINP) is a severe adverse effect of platinum- and taxane-derived anticancer drugs. The pathophysiology of CINP includes damage to neuronal networks and dysregulation of signal transduction due to abnormal Ca2+ levels. Therefore, methods that aid the recovery of neuronal networks could represent a potential treatment for CINP. We developed a mouse model of paclitaxel-induced peripheral neuropathy, representing CINP, to examine whether intrathecal injection of decursin could be effective in treating CINP. We found that decursin reduced capsaicin-induced intracellular Ca2+ levels in F11 cells and stimulated neurite outgrowth in a concentration-dependent manner. Decursin directly reduced mechanical allodynia, and this improvement was even greater with a higher frequency of injections. Subsequently, we investigated whether decursin interacts with the transient receptor potential vanilloid 1 (TRPV1). The web server SwissTargetPrediction predicted that TRPV1 is one of the target proteins that may enable the effective treatment of CINP. Furthermore, we discovered that decursin acts as a TRPV1 antagonist. Therefore, we demonstrated that decursin may be an important compound for the treatment of paclitaxel-induced neuropathic pain that functions via TRPV1 inhibition and recovery of damaged neuronal networks.
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Lin, A. Y., and N. B. Kouzminova. "Predictors of oxaliplatin-induced peripheral neuropathy in patients with advanced colorectal cancer (CRC)." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 619. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.619.
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619 Background: Chemotherapy-induced neuropathy (CINP) is one of the major dose-limiting toxicities of oxaliplatin. The purpose of this study was to identify early predictors of CIPN and investigate the feasibility of using nerve conduction studies (NCS) to monitor CINP. Methods: Under IRB-approved protocol, we systematically examined patient-reported symptoms, neurological tests and bilateral NCS of the peroneal, superficial peroneal and sural nerves every 3 weeks before each dose of oxaliplatin (75-130 mg/m2) in 12 CRC patients receiving 8 to 13 cycles of XELOX. The severity of neuropathy was graded by the NCI Common Toxicity Criteria (CTC v.4.0) and the Oxaliplatin-Specific Neurotoxicity Scale (OSNS). Results: At the end of chemotherapy three of 12 patients developed peripheral sensory neuropathy CTC grade 3, five had grade 2, and four had grade 1 (3 of them had no self-reported symptoms with loss of Achilles tendon reflexes). At the eighth cycle test only 4 patients experienced CTC grade 2 criteria, but 7 of 12 patients had paresthesias persisting between the cycles of chemotherapy (OSNS grade 2 or higher). Development of grade 2 CINP by CTC or OSNS criteria by the eights cycle of chemotherapy was not associated with the total dose of oxaliplatin received (ANOVA p = 0.86 and 0.78 accordingly), but was significantly associated with administration of concomitant medication (Spearman correlation = 0.62, p = 0.03 for OSNS and 0.6, p = 0.04 for CTC grade 2 CINP). Presence of grade 2 or higher sensory neuropathy before the 8th cycle of oxaliplatin was significantly associated with development of grade 3 CINP by the time of chemotherapy completion (Spearman correlation = 0.8, p = 0.001). The maximal CINP grade that patients have reached during chemotherapy was also significantly associated with concomitant medication use (Spearman correlation = 0.76, p = 0.004). Conclusions: Concomitant administration of medications was the only factor significantly associated with severity of CINP in our study cohort. Further study is needed to verify if it is associated with altered bioavailability of oxaliplatin. No significant financial relationships to disclose.
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Meng, Xianze, Qing Sun, Ting Miao, Qiling Liu, Hongxian Ren, and Yinglu Feng. "Involvement of spinal cannabinoid receptor type 2 in the analgesia effect of hyperbaric oxygen treatment on paclitaxel-induced neuropathic pain." Undersea and Hyperbaric Medicine 49, no. 2 (January 1, 2022): 65–75. http://dx.doi.org/10.22462/01.02.2022.6.
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Background: Chemotherapy-induced neuropathic pain (CINP) is intractable, and spinal cannabinoid receptors (CBRs) are potential therapeutic targets for CINP. Previous studies demonstrated that hyperbaric oxygen (HBO2) may contribute in alleviating specific peripheral neuropathic pain. However, neither CINP nor CBR have been clarified. We hypothesized that HBO2 is capable of alleviating CINP, and the effect could be explained by the activation of spinal CBRs. Methods: A series of paclitaxel-induced CINP models were established on male Sprague-Dawley rats. Then HBO2 treatment was administered for seven consecutive days at 2.5 atmospheres absolute. Two groups were treated with AM251 (an antagonist of CBR type-1, CBR1) or AM630 (an antagonist of CBR type-2, CBR2) respectively 30 minutes before each HBO2 treatment. The mechanical withdrawal threshold was assessed before, during and at two weeks after HBO2 treatment. Lumbar spinal cords were collected for Western blot analysis of CBR1, CBR2, GFAP and CD11b, and ELISA analysis of proinflammatory cytokines IL-1β and TNF-α. Results: A mechanical allodynia was successfully exhibited and the spinal GFAP, CD11b, IL-1β and TNF-α significantly increased after the modeling, and these effects could be further reversed by HBO2 treatment, which could be blocked by AM630, other than AM251. Conclusions: HBO2 treatment can alleviate paclitaxel-induced neuropathic pain, and be mediated by CBR2. Spinal glial cells and proinflammatory cytokines are involved in this process.
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Kim, Yeo Ok, Ji A. Song, Woong Mo Kim, and Myung Ha Yoon. "Antiallodynic Effect of Intrathecal Korean Red Ginseng in Cisplatin-Induced Neuropathic Pain Rats." Pharmacology 105, no. 3-4 (October 2, 2019): 173–80. http://dx.doi.org/10.1159/000503259.
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Background: Chemotherapy-induced neuropathic pain (CINP) is a serious side effect of chemotherapy. Korean Red Ginseng (KRG) is a popular herbal medicine in Asian countries. We examined the therapeutic potential of intrathecally administered KRG for CINP and clarified the mechanisms of action with regard to 5-hydroxytryptamine (5-HT)7 receptor at the spinal level. Methods: CINP was evoked by intraperitoneal injection of cisplatin in male Sprague-Dawley rats. After examining the effects of intrathecally administered KRG on CINP, 5-HT receptor antagonist (dihydroergocristine [DHE]) was pretreated to determine the involvement of 5-HT receptor. In addition, intrathecal 5-HT7 receptor antagonist (SB269970) was administered to define the role of 5-HT7 receptor on the effect of KRG. 5-HT7 receptor mRNA expression levels and 5-HT concentrations were examined in the spinal cord. Results: Intrathecally administered KRG produced a limited, but a dose-dependent, antiallodynic effect. Intrathecally administered DHE antagonized the antiallodynia caused by KRG. Furthermore, intrathecal SB269970 also reversed the effect of KRG. No changes in 5-HT7 receptor mRNA expression were seen in the dorsal horn of the spinal cord after cisplatin injection. After injecting cisplatin, 5-HT levels were decreased in the spinal cord, whereas those of 5-HT were increased by intrathecal KRG. Conclusions: Intrathecally administered KRG decreased CINP. In addition, spinal 5-HT7 receptors contributed to the antiallodynic effect of KRG.
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&NA;. "News from the XXIII CINP Congress." Inpharma Weekly &NA;, no. 1351 (August 2002): 14–15. http://dx.doi.org/10.2165/00128413-200213510-00035.
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Gewandter, Jennifer S., Charles E. Heckler, Katie Devine, Supriya Gupta Mohile, Oxana Palesh, Joseph Roscoe, Gary R. Morrow, Martin Joseph Bury, and Andrew Jacobs. "Pain, sleep disturbance, and fatigue symptom cluster in patients suffering from chronic chemotherapy-induced neuropathic pain (CINP)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 9113. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.9113.
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9113 Background: Various symptom cluster combinations of pain, fatigue, sleep disturbance (SD), and depression have been identified in cancer patients. The presence of symptom clusters has not been assessed in patients with persistent CINP. This exploratory analysis aimed to determine which symptoms statistically clustered with pain in cancer survivors with CINP. Methods: The University of Rochester Cancer Center Community Clinical Oncology Program recruited 461 patients with CINP > 4 (on a 0-10 scale) who had completed chemotherapy (median 7 months ago) for a pain intervention trial. At baseline, groups of highly associated symptoms that included pain were identified empirically using factor and cluster analyses of the 11 symptoms in the University of Rochester Symptom Inventory plus the Hospital Anxiety and Depression Scale (HADS) scores. To investigate if associated symptoms track together over time, multiple linear regression (MLR) analysis was performed using changes in symptom severity between baseline and week 6, controlling for gender, age, education, race, and marital status. Results: Subjects were 88% white and 71% female, and on average 61 years old. Mean (standard deviation) baseline pain, fatigue, and SD were 5.7 (2.8), 5.0 (2.7), and 4.2 (3.1), respectively; 26% of subjects had borderline or abnormal HADS scores. Factor analysis identified 3 factors that accounted for 88% of the variance. One factor included pain, fatigue, SD, but not HADS, and accounted for 37% of the variance. Variable clustering also identified pain, SD, and fatigue as 1 symptom cluster. Changes in severity of SD and fatigue (p < 0.0001), but not HADS, were associated with changes in pain (adjusted R2 = 0.168) in MLR analysis. Conclusions: Pain, fatigue, and SD were identified as a symptom cluster by factor and cluster analyses, and were found to track together over time by MLR. Since these data suggest that pain is associated with sleep quality and fatigue in patients with persistent CINP, targeting one of these symptoms may lead to reductions in the others. Future research should investigate interventions that target pain, fatigue, and SD concurrently in cancer survivors suffering from CINP.
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Liu, Yan-Wen, Ying-Jung Chen, Yen-Hao Chen, and Ming-Yen Tsai. "Therapeutic Efficacy of Traditional Chinese Medicine Syndrome-Based Formulae to Neuropathic Pain Caused by Chemotherapy." Integrative Cancer Therapies 21 (January 2022): 153473542211210. http://dx.doi.org/10.1177/15347354221121095.
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Objective: Chemotherapy-induced neuropathic pain (CINP) is a troublesome complication of anti-cancer treatment. The aim of this retrospective study was to investigate the effectiveness of classic Chinese herbal formulae (CHF) Huang Qi Gui Zhi Wu Wu Tang (HQGZWWT) and Dang Gui Si Ni Tang (DGSNT) in the treatment of CINP. Materials and Methods: Douleur Neuropathique 4 (DN4) and Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires were rated at baseline and after 3-monthly CHF treatment. Results: By searching through our medical records of all the CIPN patients from 2018 to 2019, we identified and enrolled 37 patients with Deficiency-Cold syndrome in the study, for whom the treatment of neuropathic pain by regular pharmacotherapies had failed or intolerable. At the third month evaluation with the DN4 questionnaire, 13 patients had symptomatic remission, 15 patients remained stable, and 9 patients had no response to CHF. The 3-month mean DN4 score was significantly higher than that at the baseline ( P < .001). After CHF treatment, significant differences in quality of life were noted in the physical, social, emotional, and functional well-being subscales, and in the total score, of the FACT-G ( P < .001). No adverse events or instances of disease progression were observed. Conclusions: The results of our small study are the first in the literature to show the clinical effectiveness of CHF for CINP. Combination of HQGZWWT and DGSNT is well tolerated and may offer the possibility to ameliorate CINP more than conventional care can. It merits further investigation.
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Abi-Dargham, Anissa, Christer Allgulander, O. Gureje, Rachel Jenkins, R. N. Kalaria, Brian Leonard, F. Njenga, et al. "CINP 2005 Regional Meeting, 20-22 April 2005." South African Journal of Psychiatry 11, no. 1 (April 1, 2005): 10. http://dx.doi.org/10.4102/sajpsychiatry.v11i1.92.
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List of abstract titles and authors:1. Antipsychotics across the spectrum: An overview of their mechanisms of actionAnissa Abi-Dargham2. Recent advances in the treatment of common anxiety disordersChrister Allgulander3. Psychiatry in Africa: The myths, the realities and the exoticO Gureje4. Mental Health policy developmet in Kenya and Tanznia - A DFID funded projectRachel Jenkins, David Kima, Joseph Mbatia, Frank Njenga5. Vascular factors in Alzheimer's diseaseR N Kalaria6. Depression as an immunologically based Neurodegenerative disorderBrian Leonard7. Eight years of progress in Arican PsychiatryF Njenga8. Treatment of Depression: Present and futureDr R.M. Pinder9. Imaging the Serotinergic system in impulsive aggressive personality disorder patientsLarry J Siever, Antonia S. New, Mari Goodman, Monte Buchsbaum, Erin Hazlett, Karen O'Flynn, Anissa Abi-argham, Marc Lauelle10. Mode of action of Atypical antipsychotic rugs: Focus on A2 AdrnoceptorsT.H. SvenssonNeuroscience: Selected Abstracts11. Chemical odulato of Fronto-execuitive functions: Neropsychiatric implicationsTrevor W Robbins12. Neural mechanisms of recognition memory and of social atacntProf. G Horn13. Estrogen signling after estrogen receptor ß (ERß)Jan-Ake Gustafsson14. Getting Lost: Hippocampal contributions to agerelated memory dysfunctionCarol BarnesMetals and the brain: Selected abstracts15. Modeling the contributin of iron mismanagement to Neurological disordersProf. J R C Connor16. Aluminium-triggered fibrillogenesis of B-AmyloidsProf. PZ Zatta, Dr D Drago, Mr G Tognon, Dr F RicchelliPsychiatry in Africa:17. Psychosocal aspects of Khat use among the youth of NairobiMs T M Khamis18. PTSD among motor vehicle accident survivors, KenyaDr F A Ongecha19. Psychiatric relities within African context - The Kenyan case StudyProf. D M N Ndetei20. Adolescent-parenta interactions from infancy, Nairobi KenyaDr L K Ksakhala, Prof. D M N Ndetei21. Alcohol use ong young persons: A focus group study in Southwest NigeriaO A Obeijide22. Personality disorders and personality traits among tyoe 2 Diabetic patientsProf. O El Rufaie, Dr M Sabosy, Dr M S Abuzeid23. Association of traumatic experiences with depression among Nigerian adolescentsDr O Omigbodun, Dr K BakareMs O B Yusuf, Dr O Esan24. Prevalence of depression among women attending outpatient clinics in MalawiDr M Tugumisirize, Prof. Agn, Dr Musisi25. Non-fatal suicidalbehaviour at the Johannesburg General HospitalDr M Y H Moosa, Prof. F Y Jeenah, Dr A Pillay, Pof. M Vorstere, Dr R Liebenberg26. Integrating mental health into general primary health care - Uganda's experienceDr N Kigozi27. Depression among Nigerian survivors of stroke:Prevalance and associated factorsDr F.O Fatoye Dr M A Komolafe, Dr A. O Adewuya, Dr B.A. Eegunranti Prof. M.A. Lawal28. NGO Involvement mental health care -The way forwardDr Basangwa29. Prevalen of Attenton Deficit Hyperactivity sorder among African school childrenDr E KashalaProf. T Tylleskar, Dr I Elgen, Dr K Sommerfelt30. Barriers to effective mental health care in NigeriaMs L. Kola31. Quay of life evaluation in patients with HIV-I infection with respect to the impact of Phyttherapy (Traditional Herb in Zimbabwe)M B Sebit, S K Chandiwaa, A S Latif, E Gomo, S W Acuda, F Makoni, J Vushe
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&NA;. "XX Congress of CINP (Collegium Internationale Neuro-Psychopharmacologicum)." Alzheimer Disease & Associated Disorders 10, no. 1 (March 1996): 59. http://dx.doi.org/10.1097/00002093-199603000-00017.
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Meltzer, Herbert Y. "The Rise of Psychopharmacology and the Story of CINP." Journal of Clinical Psychiatry 61, no. 1 (January 15, 2000): 65–66. http://dx.doi.org/10.4088/jcp.v61n0115b.
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Brody, E. B. "The Rise of Psychopharmacology and the Story of CINP." Journal of Nervous & Mental Disease 187, no. 11 (November 1999): 702–3. http://dx.doi.org/10.1097/00005053-199911000-00013.
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Dean, B., and T. Norman. "From Molecules to Man (CINP/ASPR Bipolar Disorder Symposium)." Acta Neuropsychiatrica 18, no. 6 (December 2006): 320. http://dx.doi.org/10.1017/s0924270800031999.
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Mastutik, Gondo, Rahmi Alia, Alphania Rahniayu, Anny Setijo Rahaju, and Renny I’tishom. "Human pappilomavirus genotype in cervical tissue of patients with Cervical Intraepithelial Neoplasia (CIN) 1, CIN 2, and CIN 3." Majalah Obstetri & Ginekologi 24, no. 3 (June 21, 2017): 74. http://dx.doi.org/10.20473/mog.v24i3.4568.
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Objectives: to determine the genotype of HPV in patients with precancerous lesions of cervical tissue.Materials and Methods: An observational study with cross sectional study of patients paraffin block CIN1, CIN2, CIN3 was conducted in Dr Soetomo Hospital. HPV DNA was extracted from paraffin blocks, then performed PCR and genotyping of HPV. The sample consisted of 28 patients with cervical tissue paraffin blocks CIN1, CIN2 and CIN3. Patients aged between 26-74 years (standard deviation 10,12).Results: HPV genotypes that infect patients with CIN1 were HPV16 and 18, CIN2 were HPV16 and 52 and CIN3 were HPV16, 67, and combined infection HPV16/67 and HPV52/67. HPV genotypes in a single infection were 26/28 (HPV16, HPV18, HPV52 and HPV67), and multiple infections were 2/28 (HPV16/67 and HPV52/67).Conclusion: The most dominant HPV genotypes infect patients with precancerous lesions of the cervix were HPV16, HPV67, HPV52, and HPV18.
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Mastutik, Gondo, Rahmi Alia, Alphania Rahniayu, Anny Setijo Rahaju, Renny I’tishom, and Suhartono Taat Putra. "Human pappilomavirus genotype in cervical tissue of patients with Cervical Intraepithelial Neoplasia (CIN) 1, CIN 2, and CIN 3." Majalah Obstetri & Ginekologi 24, no. 3 (March 31, 2018): 74. http://dx.doi.org/10.20473/mog.v24i32016.74-78.
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Objectives: to determine the genotype of HPV in patients with precancerous lesions of cervical tissue.Materials and Methods: An observational study with cross sectional study of patients paraffin block CIN1, CIN2, CIN3 was conducted in Dr Soetomo Hospital. HPV DNA was extracted from paraffin blocks, then performed PCR and genotyping of HPV. The sample consisted of 28 patients with cervical tissue paraffin blocks CIN1, CIN2 and CIN3. Patients aged between 26-74 years (standard deviation 10,12).Results: HPV genotypes that infect patients with CIN1 were HPV16 and 18, CIN2 were HPV16 and 52 and CIN3 were HPV16, 67, and combined infection HPV16/67 and HPV52/67. HPV genotypes in a single infection were 26/28 (HPV16, HPV18, HPV52 and HPV67), and multiple infections were 2/28 (HPV16/67 and HPV52/67).Conclusion: The most dominant HPV genotypes infect patients with precancerous lesions of the cervix were HPV16, HPV67, HPV52, and HPV18.
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Hoyt, M. A., T. Stearns, and D. Botstein. "Chromosome instability mutants of Saccharomyces cerevisiae that are defective in microtubule-mediated processes." Molecular and Cellular Biology 10, no. 1 (January 1990): 223–34. http://dx.doi.org/10.1128/mcb.10.1.223-234.1990.
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By using a multiply marked supernumerary chromosome III as an indicator, we isolated mutants of Saccharomyces cerevisiae that display increased rates of chromosome loss. In addition to mutations in the tubulin-encoding TUB genes, we found mutations in the CIN1, CIN2, and CIN4 genes. These genes have been defined independently by mutations causing benomyl supersensitivity and are distinct from other known yeast genes that affect chromosome segregation. Detailed phenotypic characterization of cin mutants revealed several other phenotypes similar to those of tub mutants. Null alleles of these genes caused cold sensitivity for viability. At 11 degrees C, cin mutants arrest at the mitosis stage of their cell cycle because of loss of most microtubule structure. cin1, cin2, and cin4 mutations also cause defects in two other microtubule-mediated processes, nuclear migration and nuclear fusion (karyogamy). Overproduction of the CIN1 gene product was found to cause the same phenotype as loss of function, supersensitivity to benomyl. Our findings suggest that the CIN1, CIN2, and CIN4 proteins contribute to microtubule stability either by regulating the activity of a yeast microtubule component or as structural components of microtubules.
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Hoyt, M. A., T. Stearns, and D. Botstein. "Chromosome instability mutants of Saccharomyces cerevisiae that are defective in microtubule-mediated processes." Molecular and Cellular Biology 10, no. 1 (January 1990): 223–34. http://dx.doi.org/10.1128/mcb.10.1.223.
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By using a multiply marked supernumerary chromosome III as an indicator, we isolated mutants of Saccharomyces cerevisiae that display increased rates of chromosome loss. In addition to mutations in the tubulin-encoding TUB genes, we found mutations in the CIN1, CIN2, and CIN4 genes. These genes have been defined independently by mutations causing benomyl supersensitivity and are distinct from other known yeast genes that affect chromosome segregation. Detailed phenotypic characterization of cin mutants revealed several other phenotypes similar to those of tub mutants. Null alleles of these genes caused cold sensitivity for viability. At 11 degrees C, cin mutants arrest at the mitosis stage of their cell cycle because of loss of most microtubule structure. cin1, cin2, and cin4 mutations also cause defects in two other microtubule-mediated processes, nuclear migration and nuclear fusion (karyogamy). Overproduction of the CIN1 gene product was found to cause the same phenotype as loss of function, supersensitivity to benomyl. Our findings suggest that the CIN1, CIN2, and CIN4 proteins contribute to microtubule stability either by regulating the activity of a yeast microtubule component or as structural components of microtubules.
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Coppieters, Iris. "Decreased Regional Grey Matter Volume in Women with Chronic Whiplash-Associated Disorders: Relationships with Cognitive Deficits and Disturbed Pain Processing." Pain Physician 7, no. 20;7 (November 12, 2017): E1025—E1051. http://dx.doi.org/10.36076/ppj/2017.7.e1025.
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Background: Patients with chronic whiplash-associated disorders (CWAD) are characterized by pain of traumatic origin, cognitive deficits, and central sensitization (CS). Previous neuroimaging studies revealed altered grey matter volume (GMV) in mild traumatic brain injury patients and chronic pain conditions also characterized by CS. It can therefore be hypothesized that GMV alterations also play a role in the persistent complaints of CWAD. However, brain alterations remain poorly investigated in these patients. Objectives: This study examined regional GMV alterations in patients with CWAD compared to patients with non-traumatic chronic idiopathic neck pain (CINP), who normally do not show CS at a group level, and healthy controls. Additionally, in both patient groups, relationships between regional GMV and measures of cognition as well as pain processing were assessed. Study Design: A cross-sectional case-control study. Setting: This study was performed at the Department of Rehabilitation Sciences and Physiotherapy of Ghent University in cooperation with the Ghent Institute for Functional and Metabolic Imaging. Methods: Ninety-three women (28 healthy controls, 34 CINP patients, and 31 CWAD patients) were enrolled. First, T1-weighted magnetic resonance images (MRIs) were acquired to examine GMV alterations in the brain regions involved in processing cognition and pain. Next, cognitive performance, pain cognitions, and CS symptoms were assessed. Finally, hyperalgesia and conditioned pain modulation efficacy were examined. Results: Regional GMV of the right lateral orbitofrontal cortex, left supramarginal cortex, and left posterior cingulate cortex was decreased in CWAD patients compared to healthy controls (P = 0.023; P = 0.012; P = 0.047, respectively). Additionally, GMV of the right superior parietal cortex and left posterior cingulate cortex was decreased in CWAD patients compared to CINP patients (P = 0.008; P = 0.035, respectively). Decreased regional GMV correlated with worse cognitive performance, higher maladapted pain cognitions, CS symptoms, and hyperalgesia in CWAD patients (rs = -0.515 to -0.657; P < 0.01). In CINP patients, decreased regional GMV correlated only with worse cognitive performance (rs = -0.499 to -0.619; P < 0.01), and no GMV differences compared with the controls could be revealed. Limitations: No conclusions about the causality of the observed relationships can be drawn. Conclusions: These results provide the first evidence for reduced GMV in cortical regions involved in processing cognition and pain in patients with CWAD. Accordingly, it is recommended that therapy approaches for CWAD patients should address the brain and take into account neuroplasticity of the central nervous system (CNS). Key words: Whiplash injuries, neck pain, magnetic resonance imaging, grey matter, cognitive dysfunction, pain catastrophizing, central sensitization
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Dushkin, A. D., M. S. Afanasiev, A. M. Zatevalov, V. A. Aleshkin, A. Yu Mironov, S. S. Afanasiev, Yu V. Nesvizhsky, O. Y. Borisova, T. G. Grishacheva, and A. V. Karaulov. "Digital analysis and quantitative assessment of the cervical surface with dysplasia." Russian Clinical Laboratory Diagnostics 66, no. 7 (July 16, 2021): 417–21. http://dx.doi.org/10.51620/0869-2084-2021-66-7-417-421.
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The investigation aims - a quantitative assessment of cervical surface changes with digital analysis and computer technologies in dysplasia. Colposcopy was made in 90 women from 21 to 52 years (avr. age 33,9±8,13 y.o.) with mild epithelial dysplasia (CIN1), moderate dysplasia (CIN2), severe dysplasia (CIN3). The algorithm detected indicators which provide the cervical dysplasia classification on pre cytological and pre molecular-genetic patients investigations. The outcome of an algorithm was the identification of the cervix surface condition severity by an objective quantification. The cervical dysplasia type (CIN) was classified as IndGV values. The mild dysplasia (CIN1) had IndGV=8,5, moderate dysplasia (CIN2) - IndGV=13, severe dysplasia (CIN3) - IndGV=15,6. The cervical affected surface area (IndInt) equalled 0,17 in CIN1, 0,19 in CIN2, 0,22 in CIN3. A change severity has a direct relation with a grey color value. It demonstrates quantify classification in digital analysis. The algorithm is used in real-time mode and no requires considerable material outlays. This makes it possible to use an algorithm after clinical examination and predict patient management.
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Lovejoy, C. A., X. Xu, C. E. Bansbach, G. G. Glick, R. Zhao, F. Ye, B. M. Sirbu, L. C. Titus, Y. Shyr, and D. Cortez. "Functional genomic screens identify CINP as a genome maintenance protein." Proceedings of the National Academy of Sciences 106, no. 46 (November 4, 2009): 19304–9. http://dx.doi.org/10.1073/pnas.0909345106.
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Vogel, John P., Peter Schuerman, Keith Woeste, Ingrid Brandstatter, and Joseph J. Kieber. "Isolation and Characterization of Arabidopsis Mutants Defective in the Induction of Ethylene Biosynthesis by Cytokinin." Genetics 149, no. 1 (May 1, 1998): 417–27. http://dx.doi.org/10.1093/genetics/149.1.417.
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Abstract Cytokinins elevate ethylene biosynthesis in etiolated Arabidopsis seedlings via a post-transcriptional modification of one isoform of the key biosynthetic enzyme ACC synthase. In order to begin to dissect the signaling events leading from cytokinin perception to this modification, we have isolated a series of mutants that lack the ethylene-mediated triple response in the presence of cytokinin due to their failure to increase ethylene biosynthesis. Analysis of genetic complementation and mapping revealed that these Cin mutants (cytokinin-insensitive) represent four distinct complementation groups, one of which, cin4, is allelic to the constitutive photomorphogenic mutant fus9/cop10. The Cin mutants have subtle effects on the morphology of adult plants. We further characterized the Cin mutants by analyzing ethylene biosynthesis in response to various other inducers and in adult tissues, as well as by assaying additional cytokinin responses. The cin3 mutant did not disrupt ethylene biosynthesis under any other conditions, nor did it disrupt any other cytokinin responses. Only cin2 disrupted ethylene biosynthesis in multiple circumstances. cin1 and cin2 made less anthocyanin in response to cytokinin. cin1 also displayed reduced shoot initiation in tissue culture in response to cytokinin, suggesting that it affects a cytokinin signaling element.
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Panjkovic, Milana, and Tatjana Ivkovic-Kapicl. "Ki-67 expression in squamous intraepithelial lesions of the uterine cervix." Archive of Oncology 14, no. 1-2 (2006): 23–25. http://dx.doi.org/10.2298/aoo0602023p.
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BACKGROUND: Uncontrolled cell proliferation and malignant transformation are the basic elements in the development of malignant disease including cervical cancer and its precursors. The aim of this study was to investigate the proliferative activity by using Ki-67 proliferative marker according to CIN grade. METHODS: We used immunohistochemical methods to study the expression of the proliferative marker Ki-67 in the specimens of 5 patients with normal cervical epithelium, 7 with CIN1, 13 with CIN2, and 25 patients with CIN3 grade of the cervical intraepithelial lesions. RESULTS: All cases with normal cervical epithelium and all those with CIN1 changes had negative proliferative Ki-67 index. Ki-67 positive proliferative index was found in 5 (38.46%) and 17 (68%) of patients with CIN2 and CIN3 changes respectively. There was a clear trend for increasing number of cases with positive Ki-67 index with increasing CIN grade. High significant difference of Ki-67 expression was found between patients with CIN1 and CIN2 lesions (t=2.9; p<0.01). Ki-67 positive cells were distributed only in the lower third of the epithelial layer in CIN1 cases. Seven (53.8%) and 13 (52%) of patients with CIN2 and CIN3 changes respectively, had Ki-67 positive cells in the lower and middle third of the epithelial layer, while 3 (23.1%) and 10 (40%) of cases with the same dysplastic changes had Ki-67 positive cells distributed in lower, middle and upper third of the epithelium. Difference of the Ki-67 positive cells distribution was highly significant between patient with CIN1 and CIN2 epithelial changes. CONCLUSION: The present study shows that there is statistically significant relation between proliferative activity, distribution of Ki-67 positive cells, and CIN grade. Ki-67 antigen could be a tool to identify women who are at higher risk for progression and/or recurrence of cervical squamous precancerous lesions.
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Sideri, Mario, Paola Garutti, Silvano Costa, Paolo Cristiani, Patrizia Schincaglia, Priscilla Sassoli de Bianchi, Carlo Naldoni, and Lauro Bucchi. "Accuracy of Colposcopically Directed Biopsy: Results from an Online Quality Assurance Programme for Colposcopy in a Population-Based Cervical Screening Setting in Italy." BioMed Research International 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/614035.
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Purpose. To report the accuracy of colposcopically directed biopsy in an internet-based colposcopy quality assurance programme in northern Italy.Methods. A web application was made accessible on the website of the regional Administration. Fifty-nine colposcopists out of the registered 65 logged in, viewed a posted set of 50 digital colpophotographs, classified them for colposcopic impression and need for biopsy, and indicated the most appropriate site for biopsy with a left-button mouse click on the image.Results. Total biopsy failure rate, comprising both nonbiopsy and incorrect selection of biopsy site, was 0.20 in CIN1, 0.11 in CIN2, 0.09 in CIN3, and 0.02 in carcinoma. Errors in the selection of biopsy site were stable between 0.08 and 0.09 in the three grades of CIN while decreasing to 0.01 in carcinoma. In multivariate analysis, the risk of incorrect selection of biopsy site was 1.97 for CIN2, 2.52 for CIN3, and 0.29 for carcinoma versus CIN1.Conclusions. Although total biopsy failure rate decreased regularly with increasing severity of histological diagnosis, the rate of incorrect selection of biopsy site was stable up to CIN3. In multivariate analysis, CIN2 and CIN3 had an independently increased risk of incorrect selection of biopsy site.
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Goldlust, Samuel A., Mojgan Kavoosi, Jennifer Nezzer, Mehran Kavoosi, Walter Korz, and Kenneth Deck. "Tetrodotoxin for Chemotherapy-Induced Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Dose Finding Trial." Toxins 13, no. 4 (March 25, 2021): 235. http://dx.doi.org/10.3390/toxins13040235.
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Tetrodotoxin (TTX) has emerged as a potentially efficacious agent for chemotherapy-induced neuropathic pain (CINP), a prevalent, debilitating condition often resistant to analgesics. This randomized, double-blind, dose-finding study was undertaken to explore safety and trends in efficacy of four TTX doses and to identify a dose for further study. One hundred and twenty-five patients with taxane- or platinum-related CINP received subcutaneous placebo or TTX (7.5 µg twice daily (BID), 15 µg BID, 30 µg once daily (QD), 30 µg BID) for four consecutive days. Primary outcome measure was average patient-reported Numeric Pain Rating Scale (NPRS) score during Days 21–28 post-treatment. Changes in mean NPRS score were not statistically different between cohorts, due to small trial size and influence of a few robust placebo responders. Cumulative responder analysis showed significant difference from placebo with 30 µg BID cohort using the maximum response at any timepoint (p = 0.072), 5-day (p = 0.059), 10-day (p = 0.027), and 20-day (p = 0.071) rolling averages. In secondary quality of life (QOL) outcomes, 30 µg BID cohort also differed significantly from placebo in a number of SF-36 and CIPN20 subscales. Most adverse events (AE) were mild or moderate with oral paresthesia (29.6%) and oral hypoesthesia (24.8%) as most common.
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Herrmann, W. M. "Abstract für das CINP Symposium EEG Mapping in Psychopharmacology: Anxiety/Tranquilizers." Clinical Neuropharmacology 15 (1992): 425A. http://dx.doi.org/10.1097/00002826-199201001-00222.
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Fountoulakis, Konstantinos N., Hans Jurgen Moeller, and Siegfried Kasper. "Personalised and precision psychiatry: what do the CINP bipolar guidelines suggest?" International Journal of Psychiatry in Clinical Practice 23, no. 1 (May 15, 2018): 80–81. http://dx.doi.org/10.1080/13651501.2018.1470246.
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Janowsky, David S. "Bipolar disorder-relevant abstracts of posters from the 2008 CINP congress." Current Psychiatry Reports 10, no. 6 (December 2008): 525–27. http://dx.doi.org/10.1007/s11920-008-0083-5.
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Correa, Rita Mariel, Armando Baena, Joan Valls, María Celeste Colucci, Laura Mendoza, Maryluz Rol, Carolina Wiesner, et al. "Distribution of human papillomavirus genotypes by severity of cervical lesions in HPV screened positive women from the ESTAMPA study in Latin America." PLOS ONE 17, no. 7 (July 29, 2022): e0272205. http://dx.doi.org/10.1371/journal.pone.0272205.
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The proportion of HPV16 and 18-associated cervical cancer (CC) appears rather constant worldwide (≥70%), but the relative importance of the other HR-HPV differs slightly by geographical region. Here, we studied the HPV genotype distribution of HPV positive Latin American (LA) women by histological grade, in a sub-cohort from the ESTAMPA study; we also explored the association of age-specific HPV genotypes in severe lesions. Cervical samples from 1,252 participants (854 ≤CIN1, 121 CIN2, 194 CIN3 and 83 CC) were genotyped by two PCRs-Reverse Blotting Hybridization strategies: i) Broad-Spectrum General Primers 5+/6+ and ii) PGMY9/11 PCRs. HPV16 was the most frequently found genotype in all histological grades, and increased with the severity of lesions from 14.5% in ≤ CIN1, 19.8% in CIN2, 51.5% in CIN3 to 65.1% in CC (p < 0.001). For the remaining HR-HPVs their frequency in CC did not increase when compared to less severe categories. The nonavalent vaccine HR-types ranked at the top in CC, the dominant ones being HPV16 and HPV45. HR-HPV single infection occurs, respectively, in 57.1% and 57.0% of ≤CIN1 and CIN2, increasing to 72.2% and 91.6% in CIN3 and CC (p<0.001). No association between age and HPV type was observed in CC, although the risk of HPV16 infection in CIN3 cases increased with age. Results confirm the relevance of HPV16 in the whole clinical spectrum, with a strong rise of its proportion in CIN3 and cancer. This information will be relevant in evaluating the impact of HPV vaccination, as a baseline against which to compare genotype changes in HPV type-specific distribution as vaccinated women participate in screening in LA region. Likewise, these data may help select the best HPV testing system for HPV-based efficient, affordable, and sustainable screening programmes.
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Grondin, Francis, Sébastien Freppel, Gwendolen Jull, Thomas Gérard, Teddy Caderby, and Nicolas Peyrot. "Fat Infiltration of Multifidus Muscle Is Correlated with Neck Disability in Patients with Non-Specific Chronic Neck Pain." Journal of Clinical Medicine 11, no. 19 (September 21, 2022): 5522. http://dx.doi.org/10.3390/jcm11195522.
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Chronic non-specific neck pain (CINP) is common, but the etiology remains unclear. This study aimed to examine the relationship between cervical muscle composition (cervical multifidus and longus capitis/longus colli), morphometry, range of movement, muscle function, and disability severity (Neck Disability Index) in patients with CINP. Methods: From September 2020 to July 2021, subjects underwent cervical MRI and clinical tests (cervical range of motion, cranio-cervical flexion test, neck flexor, and extensor muscle endurance). MRI analysis comprised muscle cross-sectional area, volume, and fat infiltration of multifidus and longus colli between C4 and C7 levels. Results: Twenty-five participants were included. Multiple linear regression analysis indicated that NDI was positively correlated with the volume percentage of fat infiltration of the multifidus (B = 0.496), negatively correlated with fat-free muscle volume of the multifidus normalized by subject height (B = −0.230), and accounted for 32% of the variance. There was no relationship between neck disability and longus capitis/longus colli morphology. We also found no relationship between neck disability scores, neck flexor or extensor muscle endurance, or the outcome motor control test of craniocervical flexion (p > 0.05). Conclusions: Neck disability was moderately correlated with the percentage of fat volume in the multifidus muscle and fat-free volume of the multifidus. There was no relationship between NDI scores and muscle function test outcomes or any fat or volume measures pertaining to the longus colli muscle.
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Slavkovsky, Rose C., Pooja Bansil, Manuel A. Sandoval, Jacqueline Figueroa, Doris M. Rodriguez, Jose Saul Lobo, Jose A. Jeronimo, and Silvia de Sanjosé. "Health Outcomes at 1 Year After Thermal Ablation for Cervical Precancer Among Human Papillomavirus– and Visual Inspection With Acetic Acid–Positive Women in Honduras." JCO Global Oncology, no. 6 (October 2020): 1565–73. http://dx.doi.org/10.1200/go.20.00400.
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PURPOSE This study aims to assess the detection of cervical intraepithelial lesions grades 2 and 3 (CIN2-3) at 1 year after treatment with thermal ablation among human papillomavirus (HPV)–positive and visual inspection with acetic acid (VIA)–positive women. METHODS All women screened and triaged for cervical cancer at four government health facilities in Honduras who were eligible for ablative treatment were enrolled and treated with thermal ablation. Women with confirmed CIN2-3 and a subset of women with CIN1/normal diagnoses at baseline were evaluated at 12 months. Follow-up procedures included HPV testing ( careHPV), VIA, directed biopsy (if VIA-positive), and Papanicolaou test (if HPV positive, VIA negative). Outcomes at 1 year included histologic or cytologic assessment of CIN lesions among those with any abnormal test. RESULTS Among the 319 women treated with thermal ablation, baseline histologic diagnoses were available for 317. Two (0.6%) had invasive cancer, 36 (11.4%) had CIN3, 40 (12.6%) had CIN2, and 239 (75.4%) had CIN1/normal histology. Among the 127 women eligible for follow-up, 118 (92.9%) completed all study procedures at 1 year. Overall, 98 (83.1%) had no evidence of CIN2-3 or persistent low-grade infection, 13 (11.2%) had CIN1/atypical squamous cells of undetermined significance, six (5.1%) had CIN2/high-grade squamous intraepithelial lesion, and 1 (0.8%) had a persistent CIN3. No adverse events associated with thermal ablation at 1 year were registered. CONCLUSION A high proportion of women had no evidence of CIN2-3 at 1 year after thermal ablation treatment. Thermal ablation is an alternative to cryotherapy that may facilitate greater treatment coverage and prevent unnecessary deaths from cervical cancer.
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Cho, Bum-Joo, Jeong-Won Kim, Jungkap Park, Gui-Young Kwon, Mineui Hong, Si-Hyong Jang, Heejin Bang, Gilhyang Kim, and Sung-Taek Park. "Automated Diagnosis of Cervical Intraepithelial Neoplasia in Histology Images via Deep Learning." Diagnostics 12, no. 2 (February 21, 2022): 548. http://dx.doi.org/10.3390/diagnostics12020548.
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Artificial intelligence has enabled the automated diagnosis of several cancer types. We aimed to develop and validate deep learning models that automatically classify cervical intraepithelial neoplasia (CIN) based on histological images. Microscopic images of CIN3, CIN2, CIN1, and non-neoplasm were obtained. The performances of two pre-trained convolutional neural network (CNN) models adopting DenseNet-161 and EfficientNet-B7 architectures were evaluated and compared with those of pathologists. The dataset comprised 1106 images from 588 patients; images of 10% of patients were included in the test dataset. The mean accuracies for the four-class classification were 88.5% (95% confidence interval [CI], 86.3–90.6%) by DenseNet-161 and 89.5% (95% CI, 83.3–95.7%) by EfficientNet-B7, which were similar to human performance (93.2% and 89.7%). The mean per-class area under the receiver operating characteristic curve values by EfficientNet-B7 were 0.996, 0.990, 0.971, and 0.956 in the non-neoplasm, CIN3, CIN1, and CIN2 groups, respectively. The class activation map detected the diagnostic area for CIN lesions. In the three-class classification of CIN2 and CIN3 as one group, the mean accuracies of DenseNet-161 and EfficientNet-B7 increased to 91.4% (95% CI, 88.8–94.0%), and 92.6% (95% CI, 90.4–94.9%), respectively. CNN-based deep learning is a promising tool for diagnosing CIN lesions on digital histological images.
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del Pino, Marta, Adriana Sierra, Lorena Marimon, Cristina Martí Delgado, Adriano Rodriguez-Trujillo, Esther Barnadas, Adela Saco, Aureli Torné, and Jaume Ordi. "CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions." International Journal of Molecular Sciences 20, no. 9 (May 7, 2019): 2262. http://dx.doi.org/10.3390/ijms20092262.
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Background: Squamous intraepithelial lesions/cervical intraepithelial neoplasias (SIL/CIN) are high-risk human papilloma virus (hrHPV)-related lesions which are considered as high grade (HSIL/CIN2-3) or low grade (LSIL/CIN1) lesions according to their risk of progression to cervical cancer (CC). Most HSIL/CIN2-3 are considered as transforming hrHPV infections, so truly CC precursors, although some clear spontaneously. hrHPV testing has a high sensitivity for the detection of HSIL/CIN2-3 but a relatively low specificity for identifying transforming lesions. We aimed to determine whether the combination of CADM1, MAL and miR124 promoter methylation status assessed in histological samples can be used as a biomarker in the identification of transforming HSIL/CIN lesions. Design: 131 cervical biopsies, including 8 cases with no lesion and a negative hrHPV test result (control group), 19 low-grade (L)SIL/CIN1, 30 HSIL/CIN2, 60 HSIL/CIN3, and 14 CC were prospectively collected. hrHPV was detected and genotyped using the polymerase chain reaction (PCR)-based technique SPF10 HPV LIPA. A multiplex quantitative methylation-specific PCR (qMSP) was used to identify the methylation status of the CADM1, MAL, and miR124 promoter genes. Results: Significantly higher methylation levels of CADM1, MAL and miR-124 were found in HSIL/CIN2-3 and CC compared with normal and LSIL lesions. DNA methylation of at least one gene was detected in 12.5% (1/8) of normal samples, 31.5% (6/19) of LSIL/CIN1, 83.3% (25/30) of HSIL/CIN2, 81.6% (49/60) of HSIL/CIN3 and 100% (14/14) of CC (p < 0.001). The sensitivity and specificity for HSIL/CIN2-3 and CC of having at least one methylated gene were 84.6% and 74.0%, respectively. The sensitivity and specificity of the combination of at least one methylated gene and a positive hrHPV test were 80.7% and 85.1% for HSIL/CIN2-3 and CC, respectively. Conclusions: The methylation rate of CADM1, MAL and miR124 increases with the severity of the lesion. Further research is warranted to evaluate the usefulness of these biomarkers for the identification of transforming HSIL/CIN.
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Judd, Lewis L. "Pleomorphic expressions of unipolar depressive disease: summary of the 1996 CINP President's Workshop." Journal of Affective Disorders 45, no. 1-2 (August 1997): 109–16. http://dx.doi.org/10.1016/s0165-0327(97)00064-5.
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Taguchi, Ayumi, Konan Hara, Jun Tomio, Kei Kawana, Tomoki Tanaka, Satoshi Baba, Akira Kawata, et al. "Multistate Markov Model to Predict the Prognosis of High-Risk Human Papillomavirus-Related Cervical Lesions." Cancers 12, no. 2 (January 22, 2020): 270. http://dx.doi.org/10.3390/cancers12020270.
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Cervical intraepithelial neoplasia (CIN) has a natural history of bidirectional transition between different states. Therefore, conventional statistical models assuming a unidirectional disease progression may oversimplify CIN fate. We applied a continuous-time multistate Markov model to predict this CIN fate by addressing the probability of transitions between multiple states according to the genotypes of high-risk human papillomavirus (HPV). This retrospective cohort comprised 6022 observations in 737 patients (195 normal, 259 CIN1, and 283 CIN2 patients at the time of entry in the cohort). Patients were followed up or treated at the University of Tokyo Hospital between 2008 and 2015. Our model captured the prevalence trend satisfactory, particularly for up to two years. The estimated probabilities for 2-year transition to CIN3 or more were the highest in HPV 16-positive patients (13%, 30%, and 42% from normal, CIN1, and CIN2, respectively) compared with those in the other genotype-positive patients (3.1–9.6%, 7.6–16%, and 21–32% from normal, CIN1, and CIN2, respectively). Approximately 40% of HPV 52- or 58-related CINs remained at CIN1 and CIN2. The Markov model highlights the differences in transition and progression patterns between high-risk HPV-related CINs. HPV genotype-based management may be desirable for patients with cervical lesions.
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Popiel, Aneta, Aleksandra Piotrowska, Patrycja Sputa-Grzegrzolka, Beata Smolarz, Hanna Romanowicz, Piotr Dziegiel, Marzenna Podhorska-Okolow, and Christopher Kobierzycki. "Preliminary Study on the Expression of Testin, p16 and Ki-67 in the Cervical Intraepithelial Neoplasia." Biomedicines 9, no. 8 (August 13, 2021): 1010. http://dx.doi.org/10.3390/biomedicines9081010.
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Cervical cancer is one of the most common malignant cancers in women worldwide. The 5-year survival rate is 65%; nevertheless, it depends on race, age, and clinical stage. In the oncogenesis of cervical cancer, persistent HPV infection plays a pivotal role. It disrupts the expression of key proteins as Ki-67, p16, involved in regulating the cell cycle. This study aimed to identify the potential role of testin in the diagnosis of cervical precancerous lesions (CIN). The study was performed on selected archival paraffin-embedded specimens of CIN1 (31), CIN2 (75), and CIN3 (123). Moderate positive correlation was observed between testin and Ki-67 as well as testin and p16 expression in all dysplastic lesions (r = 0.4209, r = 0.5681; p < 0.0001 for both). Statistical analysis showed stronger expression of the testin in dysplastic lesions vs. control group (p < 0.0001); moreover, expression was significantly higher in HSIL than LSIL group (p < 0.0024). In addition, a significantly stronger expression of testin was observed in CIN3 vs. CIN1 and CIN3 vs. CIN2. In our study, expression of Ki-67, p16, and testin increased gradually as the lesion progressed from LSIL to HSIL. The three markers complemented each other effectively, which may improve test sensitivity and specificity when used jointly.
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Tian, Rui, Zifeng Cui, Dan He, Xun Tian, Qinglei Gao, Xin Ma, Jian-rong Yang, et al. "Risk stratification of cervical lesions using capture sequencing and machine learning method based on HPV and human integrated genomic profiles." Carcinogenesis 40, no. 10 (May 17, 2019): 1220–28. http://dx.doi.org/10.1093/carcin/bgz094.
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Abstract From initial human papillomavirus (HPV) infection and precursor stages, the development of cervical cancer takes decades. High-sensitivity HPV DNA testing is currently recommended as primary screening method for cervical cancer, whereas better triage methodologies are encouraged to provide accurate risk management for HPV-positive women. Given that virus-driven genomic variation accumulates during cervical carcinogenesis, we designed a 39 Mb custom capture panel targeting 17 HPV types and 522 mutant genes related to cervical cancer. Using capture-based next-generation sequencing, HPV integration status, somatic mutation and copy number variation were analyzed on 34 paired samples, including 10 cases of HPV infection (HPV+), 10 cases of cervical intraepithelial neoplasia (CIN) grade and 14 cases of CIN2+ (CIN2: n = 1; CIN2-3: n = 3; CIN3: n = 9; squamous cell carcinoma: n = 1). Finally, the machine learning algorithm (Random Forest) was applied to build the risk stratification model for cervical precursor lesions based on CIN2+ enriched biomarkers. Generally, HPV integration events (11 in HPV+, 25 in CIN1 and 56 in CIN2+), non-synonymous mutations (2 in CIN1, 12 in CIN2+) and copy number variations (19.1 in HPV+, 29.4 in CIN1 and 127 in CIN2+) increased from HPV+ to CIN2+. Interestingly, ‘common’ deletion of mitochondrial chromosome was significantly observed in CIN2+ (P = 0.009). Together, CIN2+ enriched biomarkers, classified as HPV information, mutation, amplification, deletion and mitochondrial change, successfully predicted CIN2+ with average accuracy probability score of 0.814, and amplification and deletion ranked as the most important features. Our custom capture sequencing combined with machine learning method effectively stratified the risk of cervical lesions and provided valuable integrated triage strategies.
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Kelly, Helen A., Admire Chikandiwa, Bernard Sawadogo, Clare Gilham, Pamela Michelow, Olga Goumbri Lompo, Tanvier Omar, et al. "Diagnostic accuracy of cervical cancer screening and screening–triage strategies among women living with HIV-1 in Burkina Faso and South Africa: A cohort study." PLOS Medicine 18, no. 3 (March 4, 2021): e1003528. http://dx.doi.org/10.1371/journal.pmed.1003528.
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Background Cervical cancer screening strategies using visual inspection or cytology may have suboptimal diagnostic accuracy for detection of precancer in women living with HIV (WLHIV). The optimal screen and screen–triage strategy, age to initiate, and frequency of screening for WLHIV remain unclear. This study evaluated the sensitivity, specificity, and positive predictive value of different cervical cancer strategies in WLHIV in Africa. Methods and findings WLHIV aged 25–50 years attending HIV treatment centres in Burkina Faso (BF) and South Africa (SA) from 5 December 2011 to 30 October 2012 were enrolled in a prospective evaluation study of visual inspection using acetic acid (VIA) or visual inspection using Lugol’s iodine (VILI), high-risk human papillomavirus DNA test (Hybrid Capture 2 [HC2] or careHPV), and cytology for histology-verified high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) at baseline and endline, a median 16 months later. Among 1,238 women (BF: 615; SA: 623), median age was 36 and 34 years (p < 0.001), 28.6% and 49.6% ever had prior cervical cancer screening (p < 0.001), and 69.9% and 64.2% were taking ART at enrolment (p = 0.045) in BF and SA, respectively. CIN2+ prevalence was 5.8% and 22.4% in BF and SA (p < 0.001), respectively. VIA had low sensitivity for CIN2+ (44.7%, 95% confidence interval [CI] 36.9%–52.7%) and CIN3+ (56.1%, 95% CI 43.3%–68.3%) in both countries, with specificity for ≤CIN1 of 78.7% (95% CI 76.0%–81.3%). HC2 had sensitivity of 88.8% (95% CI 82.9%–93.2%) for CIN2+ and 86.4% (95% CI 75.7%–93.6%) for CIN3+. Specificity for ≤CIN1 was 55.4% (95% CI 52.2%–58.6%), and screen positivity was 51.3%. Specificity was higher with a restricted genotype (HPV16/18/31/33/35/45/52/58) approach (73.5%, 95% CI 70.6%–76.2%), with lower screen positivity (33.7%), although there was lower sensitivity for CIN3+ (77.3%, 95% CI 65.3%–86.7%). In BF, HC2 was more sensitive for CIN2+/CIN3+ compared to VIA/VILI (relative sensitivity for CIN2+ = 1.72, 95% CI 1.28–2.32; CIN3+: 1.18, 95% CI 0.94–1.49). Triage of HC2-positive women with VIA/VILI reduced the number of colposcopy referrals, but with loss in sensitivity for CIN2+ (58.1%) but not for CIN3+ (84.6%). In SA, cytology high-grade squamous intraepithelial lesion or greater (HSIL+) had best combination of sensitivity (CIN2+: 70.1%, 95% CI 61.3%–77.9%; CIN3+: 80.8%, 95% CI 67.5%–90.4%) and specificity (81.6%, 95% CI 77.6%–85.1%). HC2 had similar sensitivity for CIN3+ (83.0%, 95% CI 70.2%–91.9%) but lower specificity compared to HSIL+ (42.7%, 95% CI 38.4%–47.1%; relative specificity = 0.57, 95% CI 0.52–0.63), resulting in almost twice as many referrals. Compared to HC2, triage of HC2-positive women with HSIL+ resulted in a 40% reduction in colposcopy referrals but was associated with some loss in sensitivity. CIN2+ incidence over a median 16 months was highest among VIA baseline screen-negative women (2.2%, 95% CI 1.3%–3.7%) and women who were baseline double-negative with HC2 and VIA (2.1%, 95% CI 1.3%–3.5%) and lowest among HC2 baseline screen-negative women (0.5%, 95% CI 0.1%–1.8%). Limitations of our study are that WLHIV included in the study may not reflect a contemporary cohort of WLHIV initiating ART in the universal ART era and that we did not evaluate HPV tests available in study settings today. Conclusions In this cohort study among WLHIV in Africa, a human papillomavirus (HPV) test targeting 14 high-risk (HR) types had higher sensitivity to detect CIN2+ compared to visual inspection but had low specificity, although a restricted genotype approach targeting 8 HR types decreased the number of unnecessary colposcopy referrals. Cytology HSIL+ had optimal performance for CIN2+/CIN3+ detection in SA. Triage of HPV-positive women with HSIL+ maintained high specificity but with some loss in sensitivity compared to HC2 alone.
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Kelly, Helen, Yolanda Benavente, Miquel Angel Pavon, Silvia De Sanjose, Philippe Mayaud, and Attila Tibor Lorincz. "Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis." British Journal of Cancer 121, no. 11 (October 16, 2019): 954–65. http://dx.doi.org/10.1038/s41416-019-0593-4.
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Abstract Background To conduct a meta-analysis of performance of DNA methylation in women with high-grade cervical intraepithelial neoplasia (CIN2+). Methods Medline and Embase databases were searched for studies of methylation markers versus histological endpoints. Pooled sensitivity, specificity and positive predictive value (PPV) for CIN2+ were derived from bivariate models. Relative sensitivity and specificity for CIN2+ compared to cytology and HPV16/18 genotyping were pooled using random-effects models. Results Sixteen thousand three hundred thirty-six women in 43 studies provided data on human genes (CADM1, MAL, MIR-124-2, FAM19A4, POU4F3, EPB41L3, PAX1, SOX1) and HPV16 (L1/L2). Most (81%) studies evaluated methylation assays following a high-risk (HR)-HPV-positive or abnormal cytology result. Pooled CIN2+ and CIN3+ prevalence was 36.7% and 21.5%. For a set specificity of 70%, methylation sensitivity for CIN2+ and CIN3+ were 68.6% (95% CI: 62.9–73.8) and 71.1% (95% CI: 65.7–76.0) and PPV were 53.4% (95% CI: 44.4–62.1) and 35.0% (95% CI: 28.9–41.6). Among HR-HPV+ women, the relative sensitivity of methylation for CIN2+ was 0.81 (95% CI: 0.63–1.04) and 1.22 (95% CI: 1.05–1.42) compared to cytology of atypical squamous cells of undetermined significance, or greater (ASCUS+) and HPV16/18 genotyping, respectively, while relative specificity was 1.25 (95% CI: 0.99–1.59) and 1.03 (95% CI: 0.94–1.13), respectively. Conclusion DNA methylation is significantly higher in CIN2+ and CIN3+ compared to ≤CIN1. As triage test, DNA methylation has higher specificity than cytology ASCUS+ and higher sensitivity than HPV16/18 genotyping.
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Catalano, Martina, Giuseppe Aprile, Monica Ramello, Raffaele Conca, Roberto Petrioli, and Giandomenico Roviello. "Association between Low-Grade Chemotherapy-Induced Peripheral Neuropathy (CINP) and Survival in Patients with Metastatic Adenocarcinoma of the Pancreas." Journal of Clinical Medicine 10, no. 9 (April 23, 2021): 1846. http://dx.doi.org/10.3390/jcm10091846.
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The combination of nab-paclitaxel and gemcitabine demonstrated greater efficacy than gemcitabine alone but resulted in higher rates of chemotherapy-induced peripheral neuropathy (CINP) in patients with metastatic pancreatic cancer (mPC). We aimed to evaluate the correlation between the development of treatment-related peripheral neuropathy and the efficacy of nab-P/Gem combination in these patients. mPC patients treated with nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 as a first-line therapy were included. Treatment-related adverse events, mainly peripheral neuropathy, were categorized using the National Cancer Institute Common Toxicity Criteria scale, version 4.02. Efficacy outcomes, including overall survival (OS), progression-free survival (PSF), and disease control rate (DCR), were estimated by the Kaplan–Meier model. A total of 153 patients were analyzed; of these, 47 patients (30.7%) developed grade 1–2 neuropathy. PFS was 7 months (95% CI (6–7 months)) for patients with grade 1–2 neuropathy and 6 months (95% CI (5–6 months)) for patients without peripheral neuropathy (p = 0.42). Median OS was 13 months (95% CI (10–18 months)) and 10 months (95% CI (8–13 months)) in patients with and without peripheral neuropathy, respectively (p = 0.04). DCR was achieved by 83% of patients with grade 1–2 neuropathy and by 58% of patients without neuropathy (p = 0.03). In the multivariate analysis, grade 1–2 neuropathy was independently associated with OS (HR 0.65; 95% CI, 0.45–0.98; p = 0.03). nab-P/Gem represents an optimal first-line treatment for mPC patients. Among possible treatment-related adverse events, peripheral neuropathy is the most frequent, with different grades and incidence. Our study suggests that patients experiencing CINP may have a more favorable outcome, with a higher disease control rate and prolonged median survival compared to those without neuropathy.
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Kruse, Arnold-Jan, Jan P. A. Baak, Emiel A. Janssen, Kjell-Henning Kjellevold, Bent Fianec, Kjell Lovslett, Johan Bergh, and Stanley Robboy. "Ki67 Predicts Progression in Early CIN: Validation of a Multivariate Progression-Risk Model." Analytical Cellular Pathology 26, no. 1-2 (January 1, 2004): 13–20. http://dx.doi.org/10.1155/2004/108305.
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This study of early CIN biopsies (25 CIN1 and 65 CIN2) with long follow-up was done to validate, in a new group of patients, the value of Ki67 immuno-quantitative features to predict high CIN grade in a follow-up biopsy (often denoted to as “progression”), as described in a previous study. Each biopsy in the present study was classified with the previously described Ki67-model (consisting of the stratification index and the % positive nuclei in the middle third layer of the epithelium) as “low-risk” or “high-risk”, and matched with the follow-up outcome (progression-or-not). Furthermore, it was studied whether subjective evaluation of the Ki67 sections by experienced pathologists, who were aware of the prognostic quantitative Ki67 features, could also predict the outcome. Thirdly, the reproducibility of routine use of the quantitative Ki67-model was assessed. Fifteen cases progressed (17%) to CIN3, 2/25 CIN1 (8%) and 13/65 CIN2 (20%), indicating that CIN grade (as CIN1 or CIN2) is prognostic and that the percentage of CIN1 and CIN2 cases with progression in the present study is comparable to many previous studies. However, the quantitative Ki67 model had stronger prognostic value than CIN grade as none of the 40 “Ki67-model low-risk” patients progressed, in contrast to 15 (30%) of the 50 “Ki67-model high-risk” patients (p < 0.001). In multivariate analysis, neither CIN grade nor any of the other quantitative Ki67 features added to the abovementioned prognostic Ki67-model. Subjective analysis of the Ki67 features was also prognostic, although quantitative assessments gave better results. Routine application of the quantitative Ki67-model in CIN1 and CIN2 was well reproducible. In conclusion, the results confirm that quantitative Ki67 features have strong prognostic value for progression in early CIN lesions.
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Castle, Philip E., Rachael Adcock, Jack Cuzick, Nicolas Wentzensen, Norah E. Torrez-Martinez, Salina M. Torres, Mark H. Stoler, et al. "Relationships of p16 Immunohistochemistry and Other Biomarkers With Diagnoses of Cervical Abnormalities: Implications for LAST Terminology." Archives of Pathology & Laboratory Medicine 144, no. 6 (November 13, 2019): 725–34. http://dx.doi.org/10.5858/arpa.2019-0241-oa.
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Context.— Lower Anogenital Squamous Terminology (LAST) standardization recommended p16INK4a immunohistochemistry (p16 IHC) for biopsies diagnosed morphologically as cervical intraepithelial neoplasia (CIN) grade 2 (CIN2) to classify them as low-grade or high-grade squamous intraepithelial lesions (HSILs). Objective.— To describe the relationships of p16 IHC and other biomarkers associated with cervical cancer risk with biopsy diagnoses. Design.— A statewide, stratified sample of cervical biopsies diagnosed by community pathologists (CPs), including 1512 CIN2, underwent a consensus, expert pathologist panel (EP) review (without p16 IHC results), p16 IHC interpretation by a third pathology group, and human papillomavirus (HPV) genotyping, results of which were grouped hierarchically according to cancer risk. Antecedent cytologic interpretations were also available. Results.— Biopsies were more likely to test p16 IHC positive with increasing severity of CP diagnoses, overall (Ptrend ≤ .001) and within each HPV risk group (Ptrend ≤ .001 except for low-risk HPV [Ptrend < .010]). All abnormal grades of CP-diagnosed biopsies were more likely to test p16 IHC positive with a higher HPV risk group (Ptrend < .001), and testing p16 IHC positive was associated with higher HPV risk group than testing p16 IHC negative for each grade of CP-diagnosed biopsies (P < .001). p16 IHC–positive, CP-diagnosed CIN2 biopsies were less likely than CP-diagnosed CIN3 biopsies to test HPV16 positive, have an antecedent HSIL+ cytology, or to be diagnosed as CIN3+ by the EP (P < .001 for all). p16 IHC–positive, CP-diagnosed CIN1 biopsies had lower HPV risk groups than p16 IHC–negative, CP-diagnosed CIN2 biopsies (P < .001). Conclusions.— p16 IHC–positive, CP-diagnosed CIN2 appears to be lower cancer risk than CP-diagnosed CIN3. LAST classification of “HSIL” diagnosis, which includes p16 IHC–positive CIN2, should annotate the morphologic diagnosis (CIN2 or CIN3) to inform all management decisions, which is especially important for young (<30 years) women diagnosed with CIN2 for whom surveillance rather than treatment is recommended.
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Kruse, Arnold‐Jan, Susanne Buhr‐Wildhagen, Emiel A. Janssen, and Jan P. A. Baak. "The Relationship between Syntactic Structure Analysis Features, Histological Grade and High-Risk HPV DNA in Cervical Intraepithelial Neoplasia." Analytical Cellular Pathology 26, no. 3 (January 1, 2004): 135–41. http://dx.doi.org/10.1155/2004/592020.
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Aim: To assess the correlation between syntactic structure analysis (SSA) features, revised dysplasia grade and the presence of high‐risk human papillomavirus DNA in cervical intraepithelial neoplasia (CIN). Materials and methods: HPV polymerase chain reaction (PCR) was assessed in 101 consecutive biopsies and consensus in CIN grade between the experts occurred in 88 cases (CIN1=16, CIN2=27, CIN3=45). SSA was performed in the diagnostic histological section of the CIN lesions in these patients and SSA features were compared with the blind review CIN grade, and presence/absence of high‐risk HPV DNA. Results: One of the SSA features (points from which the surrounding surfaces has 4 edges, PECO‐4) was significantly different between all three consensus CIN grades. Many more features revealed significant differences between CIN1 and CIN2 or between CIN2 and CIN3 cases. With stepwise discriminant analysis, the best multivariate combination of features to distinguish the different CIN grades were the Maximum MST Line Length (MML) and the Area Disorder. Crude overall classification of the consensus grades with these features was 69%. The MML and the Area Disorder is also the best combination to distinguish cases with and without high‐risk HPV DNA (77% correct classifications). Conclusions: SSA features are correlated with both CIN grade and presence of high‐risk HPV DNA, but the discrimination power is not good enough to be used as a routine method for quality control of subjective grade or as a surrogate marker for high‐risk HPV DNA presence.
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Roberto Borges Bezerra, Ariani Impieri Souza, Rodrigo Alves Pinto, Miguel Angelo Martins Moreira, and Liz Maria de Almeida. "Human Papillomavirus genotypes in cervical intraepithelial lesions among women at two referral centers in Brazil." GSC Biological and Pharmaceutical Sciences 14, no. 3 (March 30, 2021): 082–89. http://dx.doi.org/10.30574/gscbps.2021.14.3.0064.
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This study aimed to describe Human Papilloma Virus (HPV) genotypes and women with cervical intraepithelial neoplasia (CIN) sociodemographic characteristics at the oncology reference centers. A secondary data of 325 records on women with CIN were analyzed from a cohort study database conducted in two public institutions in the oncological service in the Northeast of Brazil, from July 2014 to February 2016. The HPV genotype analysis was carried out on 142 through viral DNA sequence after amplifying PCR technique and compared the sequences identified in the GenBank databases. The women were predominantly 25 to 39 years old. The 325 biopsies revealed 17.6% low-grade of cervical intraepithelial lesion (CIN1) and 82.4% high-grade of cervical intraepithelial lesion (CIN2 or CIN3). Among the 142 HPV genotypes the most prevalent was HPV-16 (51.7%), followed by HPV-35 (6.9%) and HPV-45 (6.2%). HPV-18 was in only 2.1%. There was an association between HPV-16 and high-grade lesions (CIN2 or CIN3) (p=0.008). Although HPV-16 was the predominant genotype in cervical intraepithelial lesions, especially high-grade lesions (CIN2 or CIN3), HPV-35 was the second most frequent in high-grade lesions in this population. This suggests that other HPVs may be as prevalent as those commonly known in some regions.
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Fountoulakis, Konstantinos N., Lakshmi N. Yatham, Heinz Grunze, Eduard Vieta, Allan H. Young, Pierre Blier, Mauricio Tohen, Siegfried Kasper, and Hans Jurgen Moeller. "The CINP Guidelines on the Definition and Evidence-Based Interventions for Treatment-Resistant Bipolar Disorder." International Journal of Neuropsychopharmacology 23, no. 4 (December 5, 2019): 230–56. http://dx.doi.org/10.1093/ijnp/pyz064.
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Abstract Background Resistant bipolar disorder is a major mental health problem related to significant disability and overall cost. The aim of the current study was to perform a systematic review of the literature concerning (1) the definition of treatment resistance in bipolar disorder, (2) its clinical and (3) neurobiological correlates, and (4) the evidence-based treatment options for treatment-resistant bipolar disorder and for eventually developing guidelines for the treatment of this condition Materials and Methods The PRISMA method was used to identify all published papers relevant to the definition of treatment resistance in bipolar disorder and the associated evidence-based treatment options. The MEDLINE was searched to April 22, 2018. Results Criteria were developed for the identification of resistance in bipolar disorder concerning all phases. The search of the literature identified all published studies concerning treatment options. The data were classified according to strength, and separate guidelines regarding resistant acute mania, acute bipolar depression, and the maintenance phase were developed. Discussion The definition of resistance in bipolar disorder is by itself difficult due to the complexity of the clinical picture, course, and treatment options. The current guidelines are the first, to our knowledge, developed specifically for the treatment of resistant bipolar disorder patients, and they also include an operationalized definition of treatment resistance. They were based on a thorough and deep search of the literature and utilize as much as possible an evidence-based approach.
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Panjkovic, Milan, and Tatjana Ivkovic-Kapicl. "Angiogenesis in squamous precancerous cervical lesions." Vojnosanitetski pregled 64, no. 1 (2007): 7–11. http://dx.doi.org/10.2298/vsp0701007p.
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Background/Aim. Vascularisation is one of basic tumor's characteristics. Neoangiogenesis starts at the stage of the dysplastic epithelial changes, thus before the progression into invasive lesion. This study was designed to determine the relation between stromal angiogenesis and the grade of cervical intraepithelial changes (CIN). Methods. The tissue sections of 50 cone biopsies were immunohistochemically stained for CD31 antigen, a marker for endothelial cells. All microvessels along the basement membrane subtending dysplastic epithelium were counted. The mean microvessel count was calculated from the three separate fields for each specimen. All the cases were devided into four groups: normal cervical epithelium (n = 5), CIN1 (n = 7), CIN2 (n = 13), and CIN3 (n = 25). Results. The mean microvessel count (MVC) under the dysplastic epithelium was 18.1. For the patients with CIN1 changes the mean MVC was 12.9, while this number was 18.72 and 19.24 for the patients with CIN2 and CIN3 grade of epithelial changes, respectively. In a subset of the high grade lesions vascular structures were also noted in the upper layer of the epithelium. The mean MVC in the cases with the presence of these structures was 22, while this number was 12.91 in the cases without intraepithelial vessels. Although we found an increase of the mean MVC with the increase of the CIN grade, statistically significant differences were found out between CIN1 and CIN3 lesions. The mean MVC of the patients with the presence of intraepithelial vessels was statistically higher than the mean MVC of the patients without these structures. Conclusion. On the basis of the obtained results, we can conclude that the mean MVC and CIN grade positively correlated, while the number of cases with intraepithelial vessels increased with the CIN grade.
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Cuschieri, Kate, Daan Geraets, Jack Cuzick, Louise Cadman, Catherine Moore, Davy Vanden Broeck, Elisaveta Padalko, Wim Quint, and Marc Arbyn. "Performance of a Cartridge-Based Assay for Detection of Clinically Significant Human Papillomavirus (HPV) Infection: Lessons from VALGENT (Validation of HPV Genotyping Tests)." Journal of Clinical Microbiology 54, no. 9 (July 6, 2016): 2337–42. http://dx.doi.org/10.1128/jcm.00897-16.
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The Validation of Human Papillomavirus (HPV) Genotyping Tests (VALGENT) studies offer an opportunity to clinically validate HPV assays for use in primary screening for cervical cancer and also provide a framework for the comparison of analytical and type-specific performance. Through VALGENT, we assessed the performance of the cartridge-based Xpert HPV assay (Xpert HPV), which detects 14 high-risk (HR) types and resolves HPV16 and HPV18/45. Samples from women attending the United Kingdom cervical screening program enriched with cytologically abnormal samples were collated. All had been previously tested by a clinically validated standard comparator test (SCT), the GP5+/6+ enzyme immunoassay (EIA). The clinical sensitivity and specificity of the Xpert HPV for the detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and CIN3+ relative to those of the SCT were assessed as were the inter- and intralaboratory reproducibilities according to international criteria for test validation. Type concordance for HPV16 and HPV18/45 between the Xpert HPV and the SCT was also analyzed. The Xpert HPV detected 94% of CIN2+ and 98% of CIN3+ lesions among all screened women and 90% of CIN2+ and 96% of CIN3+ lesions in women 30 years and older. The specificity for CIN1 or less (≤CIN1) was 83% (95% confidence interval [CI], 80 to 85%) in all women and 88% (95% CI, 86 to 91%) in women 30 years and older. Inter- and intralaboratory agreements for the Xpert HPV were 98% and 97%, respectively. The kappa agreements for HPV16 and HPV18/45 between the clinically validated reference test (GP5+/6+ LMNX) and the Xpert HPV were 0.92 and 0.91, respectively. The clinical performance and reproducibility of the Xpert HPV are comparable to those of well-established HPV assays and fulfill the criteria for use in primary cervical cancer screening.
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Stearns, T., M. A. Hoyt, and D. Botstein. "Yeast mutants sensitive to antimicrotubule drugs define three genes that affect microtubule function." Genetics 124, no. 2 (February 1, 1990): 251–62. http://dx.doi.org/10.1093/genetics/124.2.251.
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Abstract Three new genes affecting microtubule function in Saccharomyces cerevisiae were isolated by screening for mutants displaying supersensitivity to the antimicrotubule drug benomyl. Such mutants fall into six complementation groups: TUB1, TUB2 and TUB3, the three tubulin genes of yeast, and three new genes, which we have named CIN1, CIN2 and CIN4. Mutations in each of the CIN genes were also independently isolated by screening for mutants with increased rates of chromosome loss. Strains bearing mutations in the CIN genes are approximately tenfold more sensitive than wild type to both benomyl and to the related antimicrotubule drug, nocodazole. This phenotype is recessive for all alleles isolated. The CIN1, CIN2 and CIN4 genes were cloned by complementation of the benomyl-supersensitive phenotype. Null mutants of each of the genes are viable, and have phenotypes similar to those of the point mutants. Genetic evidence for the involvement of the CIN gene products in microtubule function comes from the observation that some tubulin mutations are suppressed by cin mutations, while other tubulin mutations are lethal in combination with cin mutations. Additional genetic experiments with cin mutants suggest that the three genes act together in the same pathway or structure to affect microtubule function.
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Kremer, Wieke, Marjolein van Zummeren, Daniëlle Heideman, Birgit Lissenberg-Witte, Peter Snijders, Renske Steenbergen, Greta Dreyer, and Chris Meijer. "HPV16-Related Cervical Cancers and Precancers Have Increased Levels of Host Cell DNA Methylation in Women Living with HIV." International Journal of Molecular Sciences 19, no. 11 (October 23, 2018): 3297. http://dx.doi.org/10.3390/ijms19113297.
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Data on human papillomavirus (HPV) type-specific cervical cancer risk in women living with human immunodeficiency virus (WLHIV) are needed to understand HPV–HIV interaction and to inform prevention programs for this population. We assessed high-risk HPV type-specific prevalence in cervical samples from 463 WLHIV from South Africa with different underlying, histologically confirmed stages of cervical disease. Secondly, we investigated DNA hypermethylation of host cell genes ASCL1, LHX8, and ST6GALNAC5, as markers of advanced cervical disease, in relation to type-specific HPV infection. Overall, HPV prevalence was 56% and positivity increased with severity of cervical disease: from 28.0% in cervical intraepithelial neoplasia (CIN) grade 1 or less (≤CIN1) to 100% in invasive cervical cancer (ICC). HPV16 was the most prevalent type, accounting for 9.9% of HPV-positive ≤CIN1, 14.3% of CIN2, 31.7% of CIN3, and 45.5% of ICC. HPV16 was significantly more associated with ICC and CIN3 than with ≤CIN1 (adjusted for age, ORMH 7.36 (95% CI 2.33–23.21) and 4.37 (95% CI 1.81–10.58), respectively), as opposed to non-16 high-risk HPV types. Methylation levels of ASCL1, LHX8, and ST6GALNAC5 in cervical scrapes of women with CIN3 or worse (CIN3+) associated with HPV16 were significantly higher compared with methylation levels in cervical scrapes of women with CIN3+ associated with non-16 high-risk HPV types (p-values 0.017, 0.019, and 0.026, respectively). When CIN3 and ICC were analysed separately, the same trend was observed, but the differences were not significant. Our results confirm the key role that HPV16 plays in uterine cervix carcinogenesis, and suggest that the evaluation of host cell gene methylation levels may monitor the progression of cervical neoplasms also in WLHIV.