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| 2. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 3. |
- Alvarez, Mariano J., et al.
(författare)
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A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:7, s. 979-989
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Tidskriftsartikel (refereegranskat)abstract
- We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
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| 5. |
- Gachabayov, Mahir, et al.
(författare)
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Inadvertent laparoscopic lavage of perforated colon cancer: a systematic review
- 2024
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Ingår i: Langenbeck's archives of surgery (Print). - : SPRINGER. - 1435-2443 .- 1435-2451. ; 409:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlthough laparoscopic lavage for perforated diverticulitis with peritonitis has been grabbing the headlines, it is known that the clinical presentation of peritonitis can also be caused by an underlying perforated carcinoma. The aim of this study was to determine the incidence of patients undergoing inadvertent laparoscopic lavage of perforated colon cancer as well as the delay in cancer diagnosis.MethodsThe PubMed database was systematically searched to include all studies meeting inclusion criteria. Studies were screened through titles and abstracts with potentially eligible studies undergoing full-text screening. The primary endpoints of this meta-analysis were the rates of perforated colon cancer patients having undergone inadvertent laparoscopic lavage as well as the delay in cancer diagnosis. This was expressed in pooled rate % and 95% confidence intervals.ResultsEleven studies (three randomized, two prospective, six retrospective) totaling 642 patients met inclusion criteria. Eight studies reported how patients were screened for cancer and the number of patients who completed follow-up. The pooled cancer rate was 3.4% (0.9%, 5.8%) with low heterogeneity (Isquare2 = 34.02%) in eight studies. Cancer rates were 8.2% (0%, 3%) (Isquare2 = 58.2%) and 1.7% (0%, 4.5%) (Isquare2 = 0%) in prospective and retrospective studies, respectively. Randomized trials reported a cancer rate of 7.2% (3.1%, 11.2%) with low among-study heterogeneity (Isquare2 = 0%) and a median delay to diagnosis of 2 (1.5-5) months.ConclusionsThis systematic review found that 7% of patients undergoing laparoscopic lavage for peritonitis had perforated colon cancer with a delay to diagnosis of up to 5 months.
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| 6. |
- He, Anna, et al.
(författare)
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Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.
- 2020
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Ingår i: The Lancet. Neurology. - 1474-4465. ; 19:4, s. 307-316
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Tidskriftsartikel (refereegranskat)abstract
- High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset.In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model.We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period.High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.National Health and Medical Research Council Australia and MS Society UK.
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| 7. |
- Kajmolli, Agon, et al.
(författare)
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Robotic TAMIS: A Technical Note Comparing Si (R) versus Xi (R)
- 2021
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Ingår i: SURGICAL TECHNOLOGY INTERNATIONAL-INTERNATIONAL DEVELOPMENTS IN SURGERY AND SURGICAL RESEARCH. - : SURGICAL TECHNOLOGY INT ONLINE. - 1090-3941. ; 38
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Tidskriftsartikel (refereegranskat)abstract
- Transanal minimally invasive surgery (TAMIS) can be performed robotically assisted (R-TAMIS) for easier rectal defect suture closure particularly on the anterior rectal wall. The surgical technique described in this technical note emphasizes three safety points: 1) decreased likelihood for rectal injury when the ports are inserted into the GelPOINT (R) Path Transanal Access Platform (Applied Medical, Rancho Santa Margarita, California) on the back table rather than being inserted into the rectum; 2) decreased external collision between ports when using ports of different length; and 3) increased stabilization of pneumorectum when insufflating with an AirSeal (TM) port (Intelligent Flow System, ConMed, Utica, New York). Although R-TAMIS can be safely performed with the da Vinci (R) Si (R) or Xi (R) (Intuitive Surgical Inc., Sunnyvale, California) patient cart, the following differences are noteworthy: a) the Si (R) vertically-mounted arms design forces the patient in an uncomfortable position with asymmetrical hip flexion as opposed to the Xi (R) boom-mounted horizontal arm design; b) the 28cm circumference of each Si (R) patient cart arms operating between the patients legs offer decreased maneuvering freedom as opposed to the 19cm circumference of the Xi (R) counterparts; and c) the abduction pattern of movement of the Si (R) arms potentially increases the risk of external collision with the patients legs as opposed to the Xi (R) "jack-knife" pattern of movement.
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