A Cholecystokinin B Receptor-Specific Aptamer Does Not Activate Receptor Signaling

Targeted nanoparticles which deliver effective doses of chemotherapeutic drugs directly to pancreatic tumors could improve treatment efficacy without the toxicities associated with systemic drug administration. One protein on tumor cells that can be targeted by nanoparticles is a G-protein coupled cell surface receptor, the cholecystokinin B receptor (CCKBR). Previously, we had shown that attaching the CCKBR ligand gastrin to the surface of nanoparticles can enhance their up-take by tumors. The drawback of using gastrin is that it can also activate the receptor, causing tumor cell growth. This study shows that a DNA aptamer that binds to the CCKBR and enhances nanoparticle up-take by tumors does not activate this receptor. PANC-1 cells, a cultured human pancreatic cancer cell line, were treated for 24 h with CCKBR aptamer 1153. Cell lysates were run on Bis-Tris gels, transferred to membranes, blocked in 5% BSA and incubated overnight with primary antibodies, including antibodies directly against phosphorylated-Akt (Ser473), total Akt, and beta-actin, a protein loading control. Although the CCKBR aptamer 1153 is internalized by pancreatic cancer cells in a receptor-mediated fashion, it does not stimulate cell proliferation. Because of this, we anticipate that it will not activate CCKBR signaling. If aptamer 1153 does not activate downstream receptor signaling, our future work will test whether the aptamer could be used to specifically direct drug-containing nanoparticles to tumors, making chemotherapy treatments for pancreatic cancer patients more effective with fewer off-target effects and toxicity

Therapy with the Opioid Antagonist Naltrexone Promotes Mucosal Healing in Active Crohn's Disease: A Randomized Placebo-Controlled Trial

Abstract Background Endogenous opioid peptides have been shown to play a role in the development and/or perpetuation of inflammation. We hypothesize that the endogenous opioid system is involved in inflammatory bowel disease, and antagonism of the opioid-opioid receptor will lead to reversal of inflammation. Aims A randomized double-blind placebo-controlled study was designed to test the efficacy and safety of an opioid antagonist for 12 weeks in adults with active Crohn's disease. Methods Forty subjects with active Crohn's disease were enrolled in the study. Randomized patients received daily oral administration of 4.5-mg naltrexone or placebo. Providers and patients were masked to treatment assignment. The primary outcome was the proportion of subjects in each arm with a 70-point decline in Crohn's Disease Activity Index score (CDAI). The secondary outcome included mucosal healing based upon colonoscopy appearance and histology. Results Eighty-eight percent of those treated with naltrexone had at least a 70-point decline in CDAI scores compared to 40% of placebo-treated patients (p = 0.009). After 12 weeks, 78% of subjects treated with naltrexone exhibited an endoscopic response as indicated by a 5-point decline in the Crohn's disease endoscopy index severity score (CDEIS) from baseline compared to 28% response in placebo-treated controls (p = 0.008), and 33% achieved remission with a CDEIS score \6, whereas only 8% of those on placebo showed the same change. Fatigue was the only side effect reported that was significantly greater in subjects receiving placebo. Conclusions Naltrexone improves clinical and inflammatory activity of subjects with moderate to severe Crohn's disease compared to placebo-treated controls. Strategies to alter the endogenous opioid system provide promise for the treatment of Crohn's disease

Patterns of Failure After Radiation Therapy in Primary Spinal High-Grade Gliomas: A Single Institutional Analysis

Background Primary spinal high-grade gliomas (S-HGG) are rare aggressive tumors; radiation therapy (RT) often plays a dominant role in management. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs. Methods Patients with biopsy-proven S-HGG who received RT from 2001 to 2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan–Meier estimates were used for survival analyses. Results Twenty-nine patients were identified with a median age of 25.9 years (range 1–74 y). Four patients had GTR while 25 underwent subtotal resection or biopsy. All patients were IDH wildtype and MGMT-promoter unmethylated, where available. H3K27M mutation was present in 5 out of 10 patients tested, while one patient harbored p53 mutation. Median RT dose was 50.4 Gy (range 39.6–54 Gy) and 65% received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) of patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8 had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS was 9.7 months. On univariate analysis, age, gender, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer PFS compared to those without mutation (10.1 m vs 45.1 m) but the difference did not reach statistical significance (P = .26). Conclusions The prognosis of patients with spinal HGGs remains poor with two-thirds of the patients developing distant recurrence despite chemoradiation. Survival outcomes were similar in patients ≤ 29 years compared to adults \u3e 29 years. A better understanding of the molecular drivers of spinal HGGs is needed to develop more effective treatment options

Homeostatic Regulation of Salmonella-Induced Mucosal Inflammation and Injury by IL-23

IL-12 and IL-23 regulate innate and adaptive immunity to microbial pathogens through influencing the expression of IFN-γ, IL-17, and IL-22. Herein we define the roles of IL-12 and IL-23 in regulating host resistance and intestinal inflammation during acute Salmonella infection. We find that IL-23 alone is dispensable for protection against systemic spread of bacteria, but synergizes with IL-12 for optimal protection. IL-12 promotes the production of IFN-γ by NK cells, which is required for resistance against Salmonella and also for induction of intestinal inflammation and epithelial injury. In contrast, IL-23 controls the severity of inflammation by inhibiting IL-12A expression, reducing IFN-γ and preventing excessive mucosal injury. Our studies demonstrate that IL-23 is a homeostatic regulator of IL-12-dependent, IFN-γ-mediated intestinal inflammation

Pleiotropy of genetic variants on obesity and smoking phenotypes: Results from the Oncoarray Project of The International Lung Cancer Consortium

Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p<0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p<0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) achieved statistical significance after Bonferroni correction for multiple testing, and three suggestive SNPs (rs13021737, TMEM18; rs11583200, ELAVL4; and rs6990042, SGCZ) achieved a nominal statistical significance. Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to identify novel genetic loci of complex phenotypes

Our future: a Lancet commission on adolescent health and wellbeing.

Unprecedented global forces are shaping the health and wellbeing of the largest generation of 10 to 24 year olds in human history. Population mobility, global communications, economic development, and the sustainability of ecosystems are setting the future course for this generation and, in turn, humankind. At the same time, we have come to new understandings of adolescence as a critical phase in life for achieving human potential. Adolescence is characterised by dynamic brain development in which the interaction with the social environment shapes the capabilities an individual takes forward into adult life.3 During adolescence, an individual acquires the physical, cognitive, emotional, social, and economic resources that are the foundation for later life health and wellbeing. These same resources define trajectories into the next generation. Investments in adolescent health and wellbeing bring benefits today, for decades to come, and for the next generation. Better childhood health and nutrition, extensions to education, delays in family formation, and new technologies offer the possibility of this being the healthiest generation of adolescents ever. But these are also the ages when new and different health problems related to the onset of sexual activity, emotional control, and behaviour typically emerge. Global trends include those promoting unhealthy lifestyles and commodities, the crisis of youth unemployment, less family stability, environmental degradation, armed conflict, and mass migration, all of which pose major threats to adolescent health and wellbeing. Adolescents and young adults have until recently been overlooked in global health and social policy, one reason why they have had fewer health gains with economic development than other age groups. The UN Secretary-General's Global Strategy for Women's, Children's and Adolescents' Health initiated, in September, 2015, presents an outstanding opportunity for investment in adolescent health and wellbeing. However, because of limits to resources and technical capacities at both the national and the global level, effective response has many challenges. The question of where to make the most effective investments is now pressing for the international development community. This Commission outlines the opportunities and challenges for investment at both country and global levels (panel 1)

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer

Reducing Implant Infection in Orthopaedics (RIIiO): a pilot study for a randomised controlled trial comparing the influence of forced air versus resistive fabric warming technologies on postoperative infection rates following orthopaedic implant surgery in adults

Background Approximately 70,000 to 75,000 proximal femoral fracture repairs take place in the UK each year. Hemiarthroplasty is the preferred treatment for adults aged over 60 years. Postoperative infection affects up to 3% of patients and is the single most common reason for early return to theatre. Ultraclean ventilation was introduced to help mitigate the risk of infection, but it may also contribute to inadvertent perioperative hypothermia, which itself is a risk for postoperative infection. To counter this, active intraoperative warming is used for all procedures that take 30 min or more. Forced air warming (FAW) and resistive fabric warming (RFW) are the two principal techniques used for this purpose; they are equally effective in prevention of inadvertent perioperative hypothermia, but it is not known which is associated with the lowest infection rates. Deep surgical site infection doubles operative costs, triples investigation costs and quadruples ward costs. The Reducing Implant Infection in Orthopaedics (RIIiO) study seeks to compare infection rates with FAW versus RFW after hemiarthroplasty for hip fracture. A cost-neutral intervention capable of reducing postoperative infection rates would likely lead to a change in practice, yield significant savings for the health economy, reduce overall exposure to antibiotics and improve outcomes following hip fracture in the elderly. The findings may be transferable to other orthopaedic implant procedures and to non-orthopaedic surgical specialties. Methods RIIiO is a parallel group, open label study randomising hip fracture patients over 60 years of age who are undergoing hemiarthroplasty to RFW or FAW. Participants are followed up for 3 months. Definitive deep surgical site infection within 90 days of surgery, the primary endpoint, is determined by a blinded endpoint committee. Discussion Hemiarthroplasty carries a risk of deep surgical site infection of approximately 3%. In order to provide 90% power to demonstrate an absolute risk reduction of 1%, using a 5% significance level, a full trial would need to recruit approximately 8630 participants. A pilot study is being conducted in the first instance to demonstrate that recruitment and data management strategies are appropriate and robust before embarking on a large multi-centre trial

Evidence of off-shell Higgs boson production from ZZ leptonic decay channels and constraints on its total width with the ATLAS detector

This Letter reports on a search for off-shell production of the Higgs boson using 139 fb(-1) of pp collision data at root s = 13 TeV collected by the ATLAS detector at the Large Hadron Collider. The signature is a pair of Z bosons, with contributions from both the production and subsequent decay of a virtual Higgs boson and the interference of that process with other processes. The two observable final states are ZZ -&gt; 4l and Z Z -&gt; 2l2 nu with l = e or mu. In the ZZ -&gt; 4l final state, a dense Neural Network is used to enhance analysis sensitivity with respect to matrix element-based discrimination. The background-only hypothesis is rejected with an observed (expected) significance of 3.3 (2.2) standard deviations, representing experimental evidence for off-shell Higgs boson production. Assuming that no new particles enter the production of the virtual Higgs boson, its total width can be deduced from the measurement of its off-shell production cross-section. The measured total width of the Higgs boson is 4.5(-2.5)(+3.3) MeV, and the observed (expected) upper limit on the total width is found to be 10.5 (10.9) MeV at 95% confidence level. (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Combination of searches for invisible decays of the Higgs boson using 139 fb−1 of proton-proton collision data at root s=13 TeV collected with the ATLAS experiment

Many extensions of the Standard Model predict the production of dark matter particles at the LHC. Sufficiently light dark matter particles may be produced in decays of the Higgs boson that would appear invisible to the detector. This Letter presents a statistical combination of searches for H→invisible decays where multiple production modes of the Standard Model Higgs boson are considered. These searches are performed with the ATLAS detector using 139 fb−1of proton–proton collisions at a centre–of–mass energy of √s=13TeV at the LHC. In combination with the results at √s=7TeV and 8TeV, an upper limit on the H→invisible branching ratio of 0.107 (0.077) at the 95% confidence level is observed (expected). These results are also interpreted in the context of models where the 125GeV Higgs boson acts as a portal to dark matter, and limits are set on the scattering cross-section of weakly interacting massive particles and nucleons