COVID-19 vaccination produces exercise-responsive SARS-CoV-2 specific T-cells regardless of infection history

Background:The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)specific T-cells and neutralizing antibodies(nAbs)during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019(COVID-19).We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter nAb titers.Methods:Eighteen healthy participants completed a 20-min bout of graded cycling exercise before and/or after receiving a COVID-19 vaccine.All major leukocyte subtypes were enumerated before,during,and after exercise by flow cytometry,and immune responses to SARS-CoV-2 were determined using whole blood peptide stimulation assays,T-cell receptor(TCR)-βsequencing,and SARS-CoV-2 nAb serology.Results:COVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded exercise.However,non-infected participants had a significantly reduced mobilization of CD4+and CD8+naive T-cells,as well as CD4+central memory T-cells,after vaccination(synthetic immunity group);this was not seen after vaccination in those with prior SARS-CoV-2 infection(hybrid immunity group).Acute exercise after vaccination robustly mobilized SARS-CoV-2 specific T-cells to blood in an intensity-dependent manner.Both groups mobilized T-cells that reacted to spike protein;however,only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid antigens.nAbs increased significantly during exercise only in the hybrid immunity group.Conclusion:These data indicate that acute exercise mobilizes SARS-CoV-2 specific T-cells that recognize spike protein and increases the redistribution of nAbs in individuals with hybrid immunity.

Evaluation of the safety and effectiveness of direct oral anticoagulants and low molecular weight heparin in gastrointestinal cancer-associated venous thromboembolism

BACKGROUND Gastrointestinal cancer(GICA)is associated with a higher incidence of venous thromboembolism(VTE)compared to other solid tumors,moreover,recurrent VTE and major bleeding(MB)complications during anticoagulation treatment have an associated increase rate.GICA-VTE remains a challenging clinical scenario with MB concerns for utilization of direct oral anticoagulants(DOAC),especially with active cancer therapies.AIM To evaluate patient risk factors,effectiveness(VTE)and safety(MB)of DOACs and low molecular weight heparin(LMWH)in patients with active GICA-VTE.METHODS A retrospective chart review of patients receiving DOACs and LMWH with GICA and symptomatic or incidental VTE treated at comprehensive cancer center from November 2013 to February 2017 was performed.Inclusion criteria included active GI cancer diagnosed at any stage or treatment+/-6 mo of VTE diagnosis,whom were prescribed 6 mo or more of DOACs or LMWH.The Chi-squared test was used for overall and the Fisher exact test for pairwise comparisons of the proportions of patients experiencing recurrent VTE and MB events.Odds ratios were used to compare the relative odds of the occurrence of the outcome given exposure to the risk factor.RESULTS A total of 144 patients were prescribed anticoagulation,in which 106 fulfilled inclusion criteria apixaban(27.3%),rivaroxaban(34.9%)and enoxaparin(37.7%),and 38 were excluded.Patients median age was 66.5 years at GICA diagnosis and 67 years at CAVTE event,with 62%males,80%Caucasian,70%stage IV,pancreatic cancer(40.5%),30%Khorana Score(≥3 points),and 43.5%on active chemotherapy.Sixty-four percent of patients completed anticoagulation therapy(range 1 to 43 mo).Recurrent VTE at 6 mo was noted in 7.5%(n=3),6.8%(n=2)and 2.7%(n=1)of patients on enoxaparin,apixaban and rivaroxaban,respectively(all P=NS).MB at 6 mo were 5%(n=2)for enoxaparin,6.8%(n=2)for apixaban and 21.6%(n=8)for rivaroxaban(overall P=0.048;vs LMWH P=0.0423;all other P=NS).Significant predictors of a primary or secondary outcome for all anticoagulation therapies included:Active systemic treatment(OR=5.1,95%CI:1.3-19.3),high Khorana Score[≥3 points](OR=5.5,95%CI:1.7-17.1),active smoker(OR=6.7,95%CI:2.1-21.0),pancreatic cancer(OR=6.8,95%CI:1.9-23.2),and stage IV disease(OR=9.9,95%CI:1.2-79.1).CONCLUSION Rivaroxaban compared to apixaban and enoxaparin had a significantly higher risk of MB on GICA-VTE patients with equivocal efficacy.

Multi-institutional retrospective analysis of FOLFIRI in patients with advanced biliary tract cancers

BACKGROUND Gemcitabine plus platinum is the standard of care first-line treatment for advanced biliary tract cancers(BTC).There is no established second-line therapy,and retrospective reviews report median progression-free survival(PFS)less than 3 mo on second-line therapy.5-Fluorouracil plus irinotecan(FOLFIRI)is a commonly used regimen in patients with BTC who have progressed on gemcitabine plus platinum,though there is a paucity of data regarding its efficacy in this population.AIM To assess the efficacy of FOLFIRI in patients with biliary tract cancers.METHODS We retrospectively identified patients with advanced BTC who were treated with FOLFIRI at MD Anderson,University of Michigan and Mayo Clinic in Jacksonville.Data were collected on patient demographics,BTC subtype,response per RECIST v1.1,progression and survival.RESULTS Ninety-eight patients were included of which 74(75%)had metastatic and 24(25%)had locally advanced disease at the time of treatment with FOLFIRI.The median age was 60(range,22-86)years.The number of patients with extrahepatic cholangiocarcinoma,gall bladder cancer and intrahepatic cholangiocarcinoma were 10,17 and 71,respectively.FOLFIRI was used as 1st,2nd,3rd or 4th–Nth lines in 8,50,36 and 4 patients,respectively.Median duration on FOLFIRI in the entire cohort was 2.2(range,0.5-8.4)mo.The median PFS and overall survival were 2.4(95%confidence interval(CI):1.7-3.1)and 6.6(95%CI:4.7-8.4)mo,respectively.Median PFS for patients treated with FOLFIRI in 1st,2nd,3rd or 4th–Nth lines were 3.1,2.5,2.3 and 1.5 mo,respectively.Eighteen patients received concurrent bevacizumab(n=13)or EGFR-targeted therapy(n=5)with FOLFIRI,with a median PFS of 2.7 mo(95%CI:1.7-5.1).CONCLUSION In this largest multi-institution retrospective review of 98 patients with BTC treated with FOLFIRI,efficacy appears to be modest with outcomes similar to other cytotoxic chemotherapy regimens.

Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast

Background: Limonene, a major component in citrus oil, has demonstrated anti-cancer effects in preclinical mammary cancer models. However, the effective oral dose translates to a human dose that may not be feasible for chronic dosing. We proposed to evaluate topical application of limonene to the breast as an alternative dosing strategy. Materials and Methods: We conducted a mouse disposition study to determine whether limonene would be bioavailable in the mammary tissue after topical application. SKH-1 mice received topical or oral administration of limonene in the form of orange oil every day for 4 weeks. Plasma and mammary pads were collected 4 hrs after the final dosing. We also conducted an exploratory clinical study to evaluate the safety and feasibility of topically applied limonene in the form of orange oil to the breast. Healthy women were recruited to apply orange oil containing massage oil to their breasts daily for four weeks. Safety and feasibility were assessed by reported adverse events, clinical labs, and usage compliance. Pre and post-intervention nipple aspirate fluid (NAF) and plasma were collected for limonene concentration determination. Results: The mouse disposition study showed that topical and oral orange oil administration resulted in similar mammary tissue disposition of limonene with no clinical signs of toxicity. In the clinical study, the topical application of limonene containing massage oil to the breast was found to be safe with high levels of usage compliance for daily application, although NAF and plasma limonene concentrations were not significantly changed after the massage oil application. Conclusions: Our studies showed that limonene is bioavailable in mammary tissue after topical orange oil application in mice and this novel route of administration to the breast is safe and feasible in healthy women.

Healthy Children Arizona: Early Intervention for Prevention

The Healthy Children Arizona (HCA) program was developed to promote early, positive exposure to cancer-preventive diet, physical activity and sun safety behaviors. Five lessons delivered weekly were evaluated by classroom teachers while pre- and post-curriculum surveys examined increases in students’ understanding of concepts and self-reported behavior. The first and second graders and their teachers in ethnically diverse elementary schools (including Title 1) in Tucson and Phoenix, Arizona participated in the curriculum assessment. All 5 interactive lessons were highly rated by teachers in qualitative assessments. Aggregated analyses of pre- (n = 582) and post- (n = 588) comparison tests indicated that the HCA curriculum significantly increased students’ knowledge of each of six measured concepts (p < 0.0001), although correct choice of muscle-building foods (25%), whole grain items (78%) and target time for daily exercise (61%) were lower than desired. Mean self-reported fruit and vegetable servings eaten in the previous day increased from 3.1 ± 1.8 to 3.8 ± 1.6 (p < 0.0001). The HCA curriculum significantly improved cancer prevention knowledge among primary school children.

Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma(HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Two fully automated data-driven 3D whole-breast segmentation strategies in MRI for MR-based breast density using image registration and U-Net with a focus on reproducibility

Presence of higher breast density(BD)and persistence over time are risk factors for breast cancer.A quantitatively accurate and highly reproducible BD measure that relies on precise and reproducible whole-breast segmentation is desirable.In this study,we aimed to develop a highly reproducible and accurate whole-breast segmentation algorithm for the generation of reproducible BD measures.Three datasets of volunteers from two clinical trials were included.Breast MR images were acquired on 3T Siemens Biograph mMR,Prisma,and Skyra using 3D Cartesian six-echo GRE sequences with a fat-water separation technique.Two whole-breast segmentation strategies,utiliz-ing image registration and 3D U-Net,were developed.Manual segmentation was performed.A task-based analysis was performed:a previously developed MR-based BD measure,MagDensity,was calculated and assessed using automated and manual segmentation.The mean squared error(MSE)and intraclass correlation coefficient(ICC)between MagDensity were evaluated using the manual segmentation as a reference.The test-retest reproducibility of MagDensity derived from different breast segmentation methods was assessed using the difference between the test and retest measures(Δ_(2-1)),MSE,and ICC.The results showed that MagDensity derived by the registration and deep learning segmentation methods exhibited high concordance with manual segmentation,with ICCs of 0.986(95%CI:0.974-0.993)and 0.983(95%CI:0.961-0.992),respectively.For test-retest analysis,MagDensity derived using the regis-tration algorithm achieved the smallest MSE of 0.370 and highest ICC of 0.993(95%CI:0.982-0.997)when compared to other segmentation methods.In conclusion,the proposed registration and deep learning whole-breast segmentation methods are accurate and reliable for estimating BD.Both methods outperformed a previously developed algorithm and manual segmentation in the test-retest assessment,with the registration exhibiting superior performance for highly reproducible BD measurements.

Building bioorthogonal click-release capable artificial receptors on cancer cell surface for imaging,drug targeting and delivery

The current targeting drug delivery mainly relies on cancer cell surface receptors.However,in many cases,binding affinities between protein receptors and homing ligands is relatively low and the expression level between cancer and normal cells is not significant.Distinct from conventional targeting strategies,we have developed a general cancer targeting platform by building artificial receptor on cancer cell surface via a chemical remodeling of cell surface glycans.A new tetrazine(Tz)functionalized chemical receptor has been designed and efficiently installed on cancer cell surface as“overexpressed”biomarker through a metabolic glycan engineering.Different from the reported bioconjugation for drug targeting,the tetrazine labeled cancer cells not only locally activate TCO-caged prodrugs but also release active drugs via the unique bioorthogonal Tz-TCO click-release reaction.The studies have demonstrated that the new drug targeting strategy enables local activation of prodrug,which ultimately leads to effective and safe cancer therapy.

Prostatic Small Cell Carcinoma: Diagnosis and Management

Prostatic small cell carcinoma (PSCC) is a distinct clinical phenotype of prostate cancer. Although rare, this phenotype is highly aggressive with very high mortality. Due to this, it is imperative for clinicians to be aware of it, diagnose it early and treat it appropriately. In this article we discuss the current literature, outline a plan for its diagnosis and management, and highlight latest research on this topic.

Associations between Mother’s BMI, Fruit and Vegetable Intake and Availability, and Child’s Body Shape as Reported by Women Responding to an Annual Survey

Previous evidence indicates that a child’s body mass index (BMI) and eating behaviors are often related to the BMI and eating behaviors of his/her parents. Additionally, there is evidence suggesting that fruit and vegetable intake may impart weight control benefits. The purpose of this study was to examine the relationship between mother’s BMI and the intake/availability of fruits and vegetables in the home, as well as mother’s perceived body shape of her child. This is a cross sectional, descriptive analysis of results from a large internet-based survey of Generation X and Y mothers evaluating the role of fruit and vegetable consumption and health behaviors in US families. Mothers (n = 1469) with children under the age of 18 living in the home reported her BMI, her fruit and vegetable intake, and fruit and vegetable availability in the home. Additionally, mothers with children between the ages of 2 and 12 (n = 1177) reported her child’s body shape (using graduated images of children ranging from the 3rd - 97th percentiles of BMI). Mother’s BMI was not related to fruit or vegetable intake, though it was inversely related to fruit, but not vegetable, availability in the home. Mother’s BMI was also positively related to child’s body shape, and mother’s fruit, but not vegetable, intake was inversely related to child’s body shape. Our findings support a potential role for fruit availability promoting healthy BMI in mothers and/or healthier body shape in their children.

Novel biomarkers and the future of targeted therapies in cholangiocarcinoma:a narrative review

Background and Objectives:Cholangiocarcinoma is a highly aggressive and heterogenous group of biliary malignancies arising from any site in the biliary tree,comprising 15%of all primary liver cancers.The nature of the disease and nonspecific presentation leads to late diagnosis and ultimately poor outcomes for patients.Combination gemcitabine and cisplatin has been the standard of care for cholangiocarcinoma(CCA)since 2010,with a median overall survival of 11.7 months.The five-year survival for CCA remains 5-10%,revealing a clear need for improved treatment options.Methods:This targeted review highlights the role of next generation sequencing in CCA and the clinically relevant tumor biomarkers that have become the focus of therapeutic development.Key Content and Findings:These tumor biomarkers or actionable mutations hold the potential to enable earlier diagnosis,provide prognostic information,and guide treatment decisions for patients with CCA.Specifically,the FGFR2 fusion and IDH1 mutation have shown considerable promise in development of targeted therapies.Clinical trials with inhibitors targeting FGFR2 fusion and IDH1 mutation have created expectations that these drugs will soon enter clinical practice.Other biomarkers including KRAS and B-raf protooncogenes,Her2/neu genes,and BRCA1 and 2 tumor-suppressor genes have also been touted as potential targets for future therapies,with early data showing promise for new drug development.Conclusions:The discovery of these actionable mutations and identification of targeted therapies have challenged the notion of a“one-size fits all”for treatment of CCA,and generated optimism that these novel treatments will soon be available for patients with CCA.

Azo group-enabled metal-and oxidant-free alkenyl C-H thiolation:Access to stereodefined tetrasubstituted acyclic olefins

Metal-and oxidant-free alkenyl C–H thiolation enabled by the azo group had been established for the modular synthesis of tetrasubstituted acyclic olefins.The reaction was performed under mild reaction conditions with a broad substrate scope.The intramolecular 6-membered hydrogen-bonding network accounts for the observed excellent stereo-control.

Moving beyond hydroxychloroquine:the novel lysosomal autophagy inhibitor ROC-325 shows significant potential in preclinical studies

Autophagy is a lysosomal-mediated degradation pro-cess that controls the turnover of organelles and long-lived proteins.Outside of its role in maintaining cellu-lar homeostasis,autophagy is frequently stimulated in response to stress conditions such as those imposed by chemotherapy,nutrient deprivation,and microenviron-mental disruption.In this capacity,autophagy serves as a mechanism to generate alternative sources of metabolic fuel that promote survival when preferred energy gener-ating pathways are impaired[1].Over the past decade,stress-induced autophagy has emerged as an important driver of malignant progression and anticancer drug resistance.Virtually all classes of clinically relevant anti-cancer agents,as well as radiotherapy,have been dem-onstrated to stimulate autophagy in preclinical studies[2].In the overwhelming majority of cases,genetically or pharmacologically impairing autophagy has been shown to yield therapeutic benefit in a manner that significantly improves the efficacy of the relevant agents or modalities[3].

Catalytic asymmetric Catellani-type reaction: A powerful tool for axial chirality construction

This highlight summarizes a recent development of a catalytic enantioselective Catellani-type reaction for the synthesis of axially chiral biaryls.The chirality induction is solely governed by chiral norbornene ligand in the Pd mediated ortho C–H functionalization and ipso cross-coupling transformation.The preparative power of the methodology is demonstrated as a powerful manifold for the divergent synthesis of structurally diverse axially chiral biaryls and chiral fluorenols.