Recent advances and current challenges in CAR-T cell therapy.

Rapid advancements in the field of immunotherapy have significantly improved cancer treatments. Specifically, an individualized cell-based modality which involves the removal of some of the patient's own white blood cells, including T cells, has revolutionized research in this field. This study focuses on the recent advances and current challenges of Chimeric Antigen Receptor- T (CAR-T) cell therapy and its regulations in the United States (US) and European Union (EU). Understanding the regulatory regimes of CAR-T cell therapy is critical for researchers and manufacturers as they navigate the hurdles of bringing CAR-T cell therapy to the global market. Benefits of CAR-T cell therapy include high response rates and the potential of long-term remissions in some haematological malignancies. However, the drawbacks are still evident including high costs, adverse reactions, and limited efficacy to solid tumours. CAR-T cell therapy is rapidly advancing, with 1231 clinical trials launched globally according to www.clinicalTrial.gov . The future of CAR-T cell therapy holds enormous promise but improving its safety, effectiveness, and availability are still barriers to its successful implementation.

Anti-edematous effects of epinastine, cetirizine and its enantiomers in λ-carrageenan-induced edema in rat hind paw.

Urticaria is induced by the histamine released from mast cells which develops wheals (edema) as a visual feature. In clinical practice, second-generation histamine H1 -receptor blockers are routinely used as the first-line symptomatic treatment for urticaria. Nevertheless, not much research has directly examined the second-generation histamine H1-receptor blockers' ability to reduce edema. In this study, we directly evaluated the anti-edematous activities of three second-generation histamine H1-receptor blockers available in the market (epinastine hydrochloride, cetirizine hydrochloride, and levocetirizine hydrochloride) using a λ-carrageenan-induced footpad edema model. One hour before the induction of edema with 1% λ -carrageenan injection, all second-generation histamine H1 -receptor blockers (5, 10, 50 and 100 mg/kg) were subcutaneously administered to rats. At 0.5 and 3 hours after λ -carrageenan administration, the edema volume was evaluated using a Plethysmometer. Epinastine hydrochloride significantly suppressed the edema growth in a dose-dependent manner. Cetirizine hydrochloride showed a slight anti-edematous effect, while levocetirizine significantly inhibited the development of edema in a dose-dependent manner. On the other hand, dextrocetirizine did not prevent edema from growing. In summary, second-generation histamine H1 -receptor blockers, at least those examined in this study, may be able to reduce the clinical symptoms of urticaria associated with edema. Levocetirizine hydrochloride is also anticipated to have stronger anti-edematous effects than cetirizine hydrochloride because levocetirizine is responsible for cetirizine's anti-edematous activity.

Direct comparison of anti-inflammatory effects of 14-, 15-, and 16-membered macrolide antibiotics in experimental inflammation model induced by carrageenan in rats.

Some macrolide antibiotics, which share a basic lactone ring structure, also exhibit anti-inflammatory actions in addition to their antibacterial activities. However, no study has directly compared anti-inflammatory effects on acute inflammation among macrolide antibiotics with the distinct size of the lactone ring. In this study, we evaluated and compared the anti-inflammatory activities of four 14-membered macrolides (erythromycin, clarithromycin, roxithromycin, oleandomycin), one 15-membered macrolide (azithromycin), and three 16-membered macrolides (midecamycin, josamycin, leucomycin) using a rat carrageenan-induced footpad edema model. All macrolide antibiotics were intraperitoneally administered to rats one hour before the induction of inflammatory edema with 1% λ -carrageenan. The anti-inflammatory effects on acute inflammation were evaluated by changing the edema volume. All 14-membered and 15-membered macrolide antibiotics significantly suppressed the development of edema. Conversely, none of the 16-membered macrolide antibiotics inhibited the growth of edema. In conclusion, compared to 16-membered macrolide antibiotics, 14-membered and 15-membered macrolide antibiotics have stronger anti-inflammatory effects. Further research should be done to determine why different lactone ring sizes should have distinct anti-inflammatory effects.

Favorable clinical response and drug retention of anti-IL-6 receptor inhibitor in rheumatoid arthritis with high CRP levels: the ANSWER cohort study.

OBJECTIVE: Currently, biological disease-modifying anti-rheumatic drugs (bDMARDs) with different modes of action [tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), or cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)] are used in clinical practice to treat rheumatoid arthritis (RA). However, it is unclear which type of bDMARD is the most efficacious for a specific clinical situation. C-reactive protein (CRP) is an acute-phase reactant driven by IL-6 signalling. Here, we aimed to establish whether therapeutic efficacy differs between IL-6Ri and other bDMARDs with alternative modes of action in RA patients according to their CRP level. METHOD: RA patients treated with bDMARDs were enrolled from an observational multicentre registry in Japan. Patients were classified into three groups according to baseline CRP tertiles. The overall 3 year retention rates of each bDMARD category were assessed. The Clinical Disease Activity Index (CDAI) was also assessed before and 3, 6, and 12 months after bDMARD initiation. RESULTS: A total of 1438 RA patients were included and classified into three groups according to tertiles of baseline CRP levels (CRP1, 0-0.3; CRP2, 0.3-1.8; CRP3, 1.8-18.4 mg/dL). In CRP3, the overall 3 year drug retention rates were significantly higher for IL-6Ri than for TNFi and CTLA4-Ig (77.5 vs 48.2 vs 67.3, respectively). No significant difference was evident in terms of CDAI 12 months after bDMARD initiation in CRP1-CRP3. CONCLUSION: IL-6Ri may be a favourable therapeutic option over TNFi and CTLA4-Ig in RA patients with high CRP levels.

Major colorectal resection is feasible using a new robotic surgical platform: the first report of a case series.

BACKGROUND: The number of abdominal procedures performed via a robotic-assisted approach is increasing as potential advantages of the modality are recognised. We report the first in human case series of major colorectal resection performed using a new system, Versius®, and assess the feasibility of its use. METHODS: The initial cases performed using Versius® at a single centre in the UK were included in the study. Anonymised data were prospectively collected including patient demographics, operative details and postoperative outcomes. RESULTS: Twenty-three operations were performed, including left (n = 14) and right (n = 9)-sided colonic resections. Rectal mobilisation was performed in 13. Fifty-seven percent of the patients were male, with a malignant indication for surgery in 70% of cases. Overall mean age was 59.1 ± 15.3 (range 23-89) years. Overall mean body mass index was 28.9 ± 5.2 with a mean of 31.3 ± 4.5 for left-sided resections. The median console operating time was 166 min (range 75-320 min). All malignant cases had negative resection margins and the mean lymph node yield was 18 (SD 9.4). Only one operation (4%) was converted from robotic to open approach. Postoperative length of stay was a median of 5 days (range 3-34 days) and there were no readmissions within 30 days. CONCLUSIONS: These results compare favourably with the literature on existing robotic systems and also conventional laparoscopic surgery; hence, we believe that this series indicates the Versius® system is feasible for use in major colorectal resection. These early results from a robot-naïve centre show exciting promise for an expanding robotic market and highlight the need for further evaluation.

Patient Satisfaction With Geriatric Psychiatry Services via Video Teleconference.

OBJECTIVE: The objective for the current study is to examine patient satisfaction with geropsychiatry services provided via video telehealth. METHODS: Participants included community-dwelling older Veterans receiving geriatric psychiatry services via telehealth across regions of the Pacific Northwest and Southwestern United States. Participants completed a paper-based survey examining satisfaction with services following the completion of two medication management visits with a geropsychiatrist. RESULTS: The majority of participants (90%) reported liking or even preferring geriatric telepsychiatry, despite the experience being novel for the majority of patients. Eighty-three percent of participants reported that receiving telegeropsychiatry services was the same (n = 30) or better (n = 3) than being seen in-person. Participants saved an average of 168 driving miles (means and standard deviations = 59.2; range 2-480) each visit. CONCLUSION: The findings of the current study suggest that older adults accept and are broadly satisfied with telegeropsychiatry services. This modality of care increased access to specialty care and decreased travel hardship.

Rare structural variation of synapse and neurotransmission genes in autism.

Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.

Spot urinary protein analysis for excluding significant proteinuria in pregnancy.

The aim of this research was to compare the accuracy of urinary protein/creatinine ratio (PCR) and albumin/creatinine ratio (ACR) in defining optimal cut-off points to rule-out significant proteinuria (>300 mg/24 h) in pregnancy. The secondary outcome measure was to determine the investigation of choice to evaluate proteinuria used by maternity units in the UK. PCR and ACR were calculated on first (PCR1, ACR1) void urine samples of the 24-hour urinary protein collection (24UP). Sensitivity and specificity was calculated for different cut-off points for PCR1 and ACR1 to rule-out significant proteinuria. An online survey was sent to RCOG members questioning them on their investigation of choice to evaluate proteinuria. We concluded from our results that both PCR and ACR are good rule-out tests for significant proteinuria in pregnancy using cut-off points of <20 mg/mmol and <2.5 mg/mmol. PCR is the investigation of choice in 56% of UK units studied.

Selective CD28 blockade attenuates acute and chronic rejection of murine cardiac allografts in a CTLA-4-dependent manner.

Selective blockade of CD28 is a promising therapy to inhibit pathogenic alloimmunity. However, evaluation of this approach in transplantation has been very limited. Using a novel nonactivating single-chain Fv-based reagent (α28scFv), we have investigated the role of CD28 and cytotoxic T lymphocyte antigen 4 (CTLA-4) in a murine cardiac transplant model. Blockade of CD28 for 2 weeks after engraftment promoted allograft survival, and significantly attenuated chronic rejection when combined with transient CD154-blockade or calcineurin inhibition. Graft acceptance was associated with decreased alloantibody production, increased proportion of early graft infiltration by regulatory T cells and increased expression of regulatory dendritic cell genes. Blockade of CTLA-4 during α28scFv-based treatments led to prompt rejection in all animals and inhibited expression of forkhead box P3 (Foxp3), programmed death (PD)-1 and 2,3-indoleamine dioxygenase (IDO) in the graft. These results show that CD28 signaling during the first weeks after transplant is a pivotal mediator of pathogenic alloimmunity, and that selective CD28 blockade prolongs graft acceptance by at least two immunomodulatory mechanisms. Selective CD28 inhibition while sparing CTLA-4 is thus a promising approach to inhibit pathogenic alloimmunity.

Exonic deletion of CASP10 in a patient presenting with systemic juvenile idiopathic arthritis, but not with autoimmune lymphoproliferative syndrome type IIa.

Systemic juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly defined. To detect copy number variations, we performed single nucleotide polymorphism (SNP) array analysis in 50 patients with s-JIA. We found a 13-kb intragenic deletion of CASP10 in one patient. RT-PCR of the mRNA extracted from the patient's lymphoblastoid cells revealed that CASP10 mRNA was truncated. Sequencing the mRNA revealed that this deletion resulted in a frame shift with an early stop codon. CASP10 is known as a causative gene for autoimmune lymphoproliferative syndrome (ALPS) type IIa, another childhood syndrome of lymphadenopathy and splenomegaly associated with autoimmune haemolytic anaemia and thrombocytopenia. TCR αß(+) CD4/CD8 double-negative T cells in the peripheral blood as a diagnostic marker of ALPS were not high in this patient and lymphocyte apoptosis induced by anti-Fas antibody was normal, denying ALPS in the patient. The father and a sister of the patient showing no symptoms of ALPS or s-JIA, also had the same deletion. Furthermore, we found no other mutations of CASP10 in the other 49 s-JIA patients. These data suggest that the pathogenic significance of CASP10 mutations should be carefully evaluated in s-JIA or even ALPS type IIa in further studies.

The role of phenotypic plasticity in responses of hunted thinhorn sheep ram horn growth to changing climate conditions.

When phenotypic change occurs over time in wildlife populations, it can be difficult to determine to what degree it is because of genetic effects or phenotypic plasticity. Here, we assess phenotypic changes over time in horn length and volume of thinhorn sheep (Ovis dalli) rams from Yukon Territory, Canada. We considered 42 years of horn growth from over 50,000 growth measurements in over 8000 individuals. We found that weather explained a large proportion of the annual fluctuation in horn growth, being particularly sensitive to spring weather. Only 2.5% of variance in horn length growth could be explained by an individual effect, and thus any genetic changes over the time period could only have had a small effect on phenotypes. Our findings allow insight into the capacity for horn morphology to react to selection pressures and demonstrate the overall importance of climate in determining growth.

Optimisation of the mechanical and handling properties of an injectable calcium phosphate cement.

Calcium phosphate cements have the potential to be successful in minimally invasive surgical techniques, like that of vertebroplasty, due to their ability to be injected into a specific bone cavity. These bone cements set to produce a material similar to that of the natural mineral component in bone. Due to the ceramic nature of these materials they are highly brittle and it has been found that they are difficult to inject. This study was carried out to determine the factors that have the greatest effect on the mechanical and handling properties of an apatitic calcium phosphate cement with the use of a Design of Experiments (DoE) approach. The properties of the cement were predominantly influenced by the liquid:powder ratio and weight percent of di-sodium hydrogen phosphate within the liquid phase. An optimum cement composition was hypothesised and tested. The mechanical properties of the optimised cement were within the clinical range for vertebroplasty, however, the handling properties still require improvement.

Estimation of rates of births, deaths, and immigration from mark-recapture data.

The analysis of mark-recapture data is undergoing a period of development and expansion. Here we contribute to that by presenting a model which includes both births and immigration, as well as the usual deaths. Data come from a long-term study of the willow tit (Parus montanus), where we can assume that all births are recorded, and hence immigrants can also be identified as birds captured as adults for the first time. We model the rates of immigration, birth rate per parent, and death rates of juveniles and adults. Using a hierarchical model allows us to incorporate annual variation in these parameters. The model is fitted to the data using Markov chain Monte Carlo, as a Bayesian analysis. In addition to the model fitting, we also check several aspects of the model fit, in particular whether survival varies with age or immigrant status, and whether capture probability is affected by previous capture history. The latter check is important, as independence of capture histories is a key assumption that simplifies the model considerably. Here we find that the capture probability depends strongly on whether the individual was captured in the previous year.

Lunar periodicity and the timing of river entry in Atlantic salmon Salmo salar.

Historical catch records of Atlantic salmon Salmo salar from three rivers discharging to the Baltic Sea in an area free from tides and from strong effects of the moon on illumination were analysed to investigate whether timing of S. salar river entry was associated with lunar cycles directly. Although a significant effect of lunar phase on river entry was detected, with more fish entering rivers around the full moon than other phases, the effect of the lunar cycle was very small compared with other sources of variation. Hence, the biological role of lunar cycle as a determinant of the timing of S. salar runs in the investigated populations was negligible, suggesting that lunar cycle per se does not play a role in the timing of S. salar river entry.

Under-Recognition of Fractures as Osteoporosis Indicators.

After the first fracture, the risk of subsequent fractures increases significantly. Medical treatment can reduce the risk of a second fracture by about 50%, but many older adults do not receive osteoporosis medication following their first fracture. This observational study aimed to understand primary care management patterns of older adults after osteoporotic fractures at the Miami Veterans Affairs (VA) Healthcare System. A retrospective review of 219 fracture cases selected by International Classification of Disease (ICD-9) codes between October 2015 and September 2016 identified 114 individuals age ≥50 years who had a non-traumatic fracture code entered in their medical record for the first time. Among them, 72 (63%) did not undergo a bone mineral density (BMD) test or receive treatment in the 12 months following their fracture. Of the 40 individuals who had a BMD test post-fracture, 17 (100%) received or were considered for anti-osteoporosis treatment if their T-score indicated osteoporosis (T-score ≤-2.5), but only 8/23 (35%) if the T-score was >-2.5. Physicians are more likely to prescribe osteoporosis therapy based on a BMD T-score diagnosis of osteoporosis, rather than a clinical diagnosis of osteoporosis based on a low-trauma fracture. A change in practice patterns is necessary to decrease the incidence of fractures.

Climate-driven spatial dynamics of plague among prairie dog colonies.

We present a Bayesian hierarchical model for the joint spatial dynamics of a host-parasite system. The model was fitted to long-term data on regional plague dynamics and metapopulation dynamics of the black-tailed prairie dog, a declining keystone species of North American prairies. The rate of plague transmission between colonies increases with increasing precipitation, while the rate of infection from unknown sources decreases in response to hot weather. The mean annual dispersal distance of plague is about 10 km, and topographic relief reduces the transmission rate. Larger colonies are more likely to become infected, but colony area does not affect the infectiousness of colonies. The results suggest that prairie dog movements do not drive the spread of plague through the landscape. Instead, prairie dogs are useful sentinels of plague epizootics. Simulations suggest that this model can be used for predicting long-term colony and plague dynamics as well as for identifying which colonies are most likely to become infected in a specific year.

Comparative studies of quantitative trait and neutral marker divergence: a meta-analysis.

Comparative studies of quantitative genetic and neutral marker differentiation have provided means for assessing the relative roles of natural selection and random genetic drift in explaining among-population divergence. This information can be useful for our fundamental understanding of population differentiation, as well as for identifying management units in conservation biology. Here, we provide comprehensive review and meta-analysis of the empirical studies that have compared quantitative genetic (Q(ST)) and neutral marker (F(ST)) differentiation among natural populations. Our analyses confirm the conclusion from previous reviews - based on ca. 100% more data - that the Q(ST) values are on average higher than F(ST) values [mean difference 0.12 (SD 0.27)] suggesting a predominant role for natural selection as a cause of differentiation in quantitative traits. However, although the influence of trait (life history, morphological and behavioural) and marker type (e.g. microsatellites and allozymes) on the variance of the difference between Q(ST) and F(ST) is small, there is much heterogeneity in the data attributable to variation between specific studies and traits. The latter is understandable as there is no reason to expect that natural selection would be acting in similar fashion on all populations and traits (except for fitness itself). We also found evidence to suggest that Q(ST) and F(ST) values across studies are positively correlated, but the significance of this finding remains unclear. We discuss these results in the context of utility of the Q(ST)-F(ST) comparisons as a tool for inferring natural selection, as well as associated methodological and interpretational problems involved with individual and meta-analytic studies.

Bayesian approaches in evolutionary quantitative genetics.

The study of evolutionary quantitative genetics has been advanced by the use of methods developed in animal and plant breeding. These methods have proved to be very useful, but they have some shortcomings when used in the study of wild populations and evolutionary questions. Problems arise from the small size of data sets typical of evolutionary studies, and the additional complexity of the questions asked by evolutionary biologists. Here, we advocate the use of Bayesian methods to overcome these and related problems. Bayesian methods naturally allow errors in parameter estimates to propagate through a model and can also be written as a graphical model, giving them an inherent flexibility. As packages for fitting Bayesian animal models are developed, we expect the application of Bayesian methods to evolutionary quantitative genetics to grow, particularly as genomic information becomes more and more associated with environmental data.

DNA damage in the nucleosome core is refractory to repair by human excision nuclease.

To investigate the effect of nucleosomes on nucleotide excision repair in humans, we prepared a mononucleosome containing a (6-4) photoproduct in the nucleosome core and examined its repair with the reconstituted human excision nuclease system and with cell extracts. Nucleosomal DNA is repaired at a rate of about 10% of that for naked DNA in both systems. These results are in agreement with in vivo data showing a considerably slower rate of repair of overall genomic DNA relative to that for transcriptionally active DNA. Furthermore, our results indicate that the first-order packing of DNA in nucleosomes is a primary determinant of slow repair of DNA in chromatin.

Bias and precision in QST estimates: problems and some solutions.

Comparison of population differentiation in neutral marker genes and in genes coding quantitative traits by means of F(ST) and Q(ST) indexes has become commonplace practice. While the properties and estimation of F(ST) have been the subject of much interest, little is known about the precision and possible bias in Q(ST) estimates. Using both simulated and real data, we investigated the precision and bias in Q(ST) estimates and various methods of estimating the precision. We found that precision of Q(ST) estimates for typical data sets (i.e., with <20 populations) was poor. Of the methods for estimating the precision, a simulation method, a parametric bootstrap, and the Bayesian approach returned the most precise estimates of the confidence intervals.