Over the past couple of decades, antibody-drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ...ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics.
Some preclinical and clinical studies have demonstrated the positive impact of probiotic supplementation on depressive symptoms. This paper aims to provide an updated meta-analysis on the topic.
...Using the keywords probiotics OR gut OR microflora OR microbiome OR bacteria OR yeast OR yoghurt OR lactobacillus OR bifidobacterium AND mood OR depression OR MDD OR suicide, a preliminary search on the PubMed, Ovid, Clinical Trials Register of the Cochrane Collaboration Depression, Anxiety and Neurosis Group (CCDANTR) and Cochrane Field for Complementary Medicine database yielded 917 papers published in English between 1-Jan-1960 and 1-June-2017.
10 clinical trials with a total of 1349 patients were reviewed, comparing the use of probiotics to placebo controls. There was no significant difference in mood between the treatment and placebo group post-intervention as the standardized mean difference (SMD) was −0.128 (95% CI −0.261 to 0.00463, P=0.059). A separate subgroup analysis of studies conducted in healthy versus depressed individuals found significant improvements in the moods of individuals with mild to moderate depressive symptoms (SMD −0.684, 95% CI −1.296 to −0.0712, P=0.029) and non-significant effects in healthy individuals (SMD −0.0999, 95% CI −0.235 to 0.0348, P=0.146).
Inter-study discrepancies with respect to probiotic dosing, bacterial strains and strain combinations limit the comparability of current clinical trials. Furthermore, majority of existing RCTs were conducted in healthy individuals, making it difficult to extrapolate the results to depressed individuals.
Probiotic supplementation has an overall insignificant effect on mood. Future studies should be conducted on more patients with clinically diagnosed depression.
•10 randomized, controlled trials with a total of 1349 patients were reviewed.•The use of probiotics was compared to placebo controls.•Probiotic supplementation has an overall insignificant effect on mood.•Future studies should be conducted on more patients with clinically diagnosed MDD.
Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects ...are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients.
FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129).
Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95;
< .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17;
< .0001) and 0.02 (95% CI, < 0.01 to 0.05;
= .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively.
Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to ...advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management.
Two groups of mice were exposed to stimulus discrimination training and testing under different motivational conditions to study interactions between motivating operations (MOs) during initial ...discrimination training and MOs when performance is tested following training. One group received all discrimination training sessions under 24-h food deprivation while the other received all sessions under 0-h food deprivation. The number of responses allowed during discrimination training sessions was limited such that the two groups experienced the same number of response-outcome contingencies. The groups then received two post-discrimination training tests: one conducted under 24-h food deprivation and the other conducted under 0-h food deprivation. Results indicated no difference between groups in terms of discrimination ratio. However, subjects trained under 24-h deprivation made more responses in the 24-h test, while subjects trained under 0-h deprivation made more responses in the 0-h test. These results are discussed in terms of motivational state-dependent learning.
•Discriminative and motivational features of context interact in evoking operant behavior.•Shifts in motivation from discrimination training to testing can affect performance.•Mice received operant discrimination training under 24-h or 0-h food deprivation.•Post-discrimination performance was tested under 24-h and 0-h deprivation.•Discriminative and motivational functions of the test contexts contributed to test results.
Survival outcomes for patients with advanced ovarian cancer remain poor despite advances in chemotherapy and surgery. Platinum-based systemic chemotherapy can result in a response rate of up to 80%, ...but most patients will have recurrence and die from the disease. Recently, the DNA-repair-directed precision oncology strategy has generated hope for patients. The clinical use of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA germ-line-deficient and/or platinum-sensitive epithelial ovarian cancers has improved survival. However, the emergence of resistance is an ongoing clinical challenge. Here, we review the current clinical state of PARP inhibitors and other clinically viable targeted approaches in epithelial ovarian cancers.
Sickle cell disease affects the whole body through acute and chronic organ damage and results in significant physical and neurological constraints. The report by Cseh et al. demonstrates in a ...retrospective multinational study that allogeneic haematopoietic stem cell transplantation from HLA-identical siblings using a contemporary conditioning regimen is safe and effective in more than 96% of patients. Commentary on: Cseh et al. Busulfan-fludarabine- or treosulfan-fludarabine-based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties. Br J Haematol 2024;204:e1-e5. Correction added on 23 November 2023, after first online publication: In the preceding sentence, the article title and doi have been updated in this version..
ABSTRACT We identify 885,503 type 1 quasar candidates to using the combination of optical and mid-IR photometry. Optical photometry is taken from the Sloan Digital Sky Survey-III: Baryon Oscillation ...Spectroscopic Survey (SDSS-III/BOSS), while mid-IR photometry comes from a combination of data from the Wide-field Infrared Survey Explorer (WISE) "AllWISE" data release and several large-area Spitzer Space Telescope fields. Selection is based on a Bayesian kernel density algorithm with a training sample of 157,701 spectroscopically confirmed type 1 quasars with both optical and mid-IR data. Of the quasar candidates, 733,713 lack spectroscopic confirmation (and 305,623 are objects that we have not previously classified as photometric quasar candidates). These candidates include 7874 objects targeted as high-probability potential quasars with (of which 6779 are new photometric candidates). Our algorithm is more complete to than the traditional mid-IR selection "wedges" and to quasars than the SDSS-III/BOSS project. Number counts and luminosity function analysis suggest that the resulting catalog is relatively complete to known quasars and is identifying new high-z quasars at . This catalog paves the way for luminosity-dependent clustering investigations of large numbers of faint, high-redshift quasars and for further machine-learning quasar selection using Spitzer and WISE data combined with other large-area optical imaging surveys.
In dual-phase time-projection chambers there are photosensor arrays arranged to allow for inference of the positions of interactions within the detector. If there is a gap in data left by a broken or ...saturated photosensors, the inference of the position is less precise and less accurate. As we are unable to repair or replace photosensors once the experiment has begun, we develop methods to estimate the missing signals. Our group is developing a probabilistic graphical model of the correlations between the number of photons detected by adjacent photosensors that represents the probability distribution over photons detected as a Poisson distribution. Determining the posterior probability distribution over a number of photons detected by a sensor then requires integration over a multivariate Poisson distribution, which is computationally intractable for high-dimensions. In this work, we present an approach to quickly calculate and integrate over a multidimensional Poisson distribution. Our approach uses Zarr, a Python array compression package, to manage large multi-dimensional arrays and approximates the log factorial to quickly calculate the Poisson distribution without overflow.
Although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for patients with Fanconi anemia (FA), published series mostly refer to single-center experience ...with limited numbers of patients. We analyzed results in 795 patients with FA who underwent first HSCT between May 1972 and January 2010. With a 6-year median follow-up, overall survival was 49% at 20 years (95% confidence interval, 38-65 years). Better outcome was observed for patients transplanted before the age of 10 years, before clonal evolution (ie, myelodysplastic syndrome or acute myeloid leukemia), from a matched family donor, after a conditioning regimen without irradiation, the latter including fludarabine. Chronic graft-versus-host disease and secondary malignancy were deleterious when considered as time-dependent covariates. Age more than 10 years at time of HSCT, clonal evolution as an indication for transplantation, peripheral blood as source of stem cells, and chronic graft-versus-host disease were found to be independently associated with the risk for secondary malignancy. Changes in transplant protocols have significantly improved the outcome of patients with FA, who should be transplanted at a young age, with bone marrow as the source of stem cells.
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