Characteristics Associated With Functional Changes During Systemic Cancer Treatments: A Systematic Review Focused on Older Adults.

BACKGROUND: Maintaining functional status is important to older adults with cancer, but data are limited on how systemic treatments affect functional status. We systematically reviewed changes in functional status during systemic cancer treatments and identified characteristics associated with functional decline and improvement. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Register of Controlled Trials for articles examining characteristics associated with functional changes in older adults during systemic cancer treatment published in English between database inception and January 11, 2019 (PROSPERO CRD42019123125). Findings were summarized with descriptive statistics. Study characteristics between older adult-specific and non-older adult-specific studies were compared using the Fisher exact test. RESULTS: We screened 15,244 titles/abstracts and 519 full texts. The final analysis included 44 studies, which enrolled >8,400 patients; 39% of studies focused on older adults (1 study enrolled adults aged ≥60 years, 10 enrolled adults aged ≥65 years, and 6 enrolled adults aged ≥70 years). Almost all studies (98%) used patient-reported outcomes to measure functional status; only 20% used physical performance tests. Reporting of functional change was heterogeneous, with 48% reporting change scores. Older adult-specific studies were more likely to analyze functional change dichotomously (29% vs 4%; P=.008). Functional decline ranged widely, from 6% to 90%. The most common patient characteristics associated with functional decline were older age (n=7 studies), worse performance status (n=4), progressive disease status (n=4), pain (n=4), anemia (n=4), and worse nutritional status (n=4). Twelve studies examined functional improvement and identified 11 unique associated characteristics. CONCLUSIONS: Functional decline is increasingly recognized as an important outcome in older adults with cancer, but definitions and analyses are heterogeneous, leading to a wide range of prevalence. To identify patients at highest risk of functional decline during systemic cancer treatments, trials need to routinely analyze functional outcomes and measure characteristics associated with decline (eg, nutrition).

Septic arthritis due to non-tuberculous mycobacterium without effusion.

Septic arthritis is an important but difficult to make diagnosis that leads to significant morbidity and mortality. Joint effusion is generally accepted to be a highly sensitive finding in septic arthritis; however, final diagnosis requires synovial fluid studies. Without a significant joint effusion, it is difficult to obtain synovial fluid. In this case report, we describe the presentation and diagnosis of septic arthritis in the first MTP due to mycobacterium chelonae in a 69 year old man with a history of gout and immunosuppression due to a heart transplant. There was notably no significant effusion in the joint on clinical examination or bedside ultrasound. As the patient was immunosuppressed, arthrocentesis was performed under ultrasound guidance. A needle was clearly visualized in the joint; however, minimal synovial fluid was obtained. The fluid grew Mycobacterium chelonae in culture. Subsequent joint washout revealed purulent synovial fluid that grew out the same bacteria. This case emphasizes the importance of obtaining synovial fluid to evaluate for septic arthritis, even when joint effusion is absent. Ultrasound guidance can facilitate this.

Undifferentiated Dyspnea with Point-of-Care Ultrasound, Primary Emergency Physician Compared with a Dedicated Emergency Department Ultrasound Team.

BACKGROUND: Emergency physicians (EPs) perform critical actions while operating with diagnostic uncertainty. Point-of-care ultrasound (POCUS) is useful in evaluation of dyspneic patients. In prior studies, POCUS is often performed by ultrasound (US) teams without patient care responsibilities. OBJECTIVES: This study evaluates the effectiveness of POCUS in narrowing diagnostic uncertainty in dyspneic patients when performed by treating EPs vs. separate US teams. METHODS: This multicenter, prospective noninferiority cohort study investigated the effect of a POCUS performing team in patient encounters for dyspnea. Before-and-after surveys assessing medical decision-making were administered to attending physicians. Primary outcome was change in most likely diagnosis after POCUS. This was assessed for noninferiority between encounters where the primary or US team performed POCUS. Secondary outcomes included change in differential diagnosis, confidence in diagnosis, interventions considered, and image quality. RESULTS: There were 156 patient encounters analyzed. In the primary team group, most likely diagnosis changed in 40% (95% confidence interval 28-52%) of encounters vs. 32% (95% confidence interval 22-41%) in the US team group. This was noninferior using an a priori specified margin of 20% (p < .0001). Post-POCUS differential decreased by a mean 1.8 diagnoses and was equivalent within a margin of 0.5 diagnoses between performing teams (p = 0.034). Other outcomes were similar between groups. CONCLUSION: POCUS performed by primary teams was noninferior to POCUS performed by US teams for changing the most likely diagnosis, and equivalent when considering mean reduction in number of diagnoses. POCUS performed by treating EPs reduces cognitive burden in dyspneic patients.

Low carbohydrate diets containing soy protein and fish oil slow the growth of established NNK-induced lung tumors.

We recently found that a diet composed of 15% of total calories as carbohydrate (CHO), primarily as amylose, 35% soy protein and 50% fat, primarily as fish oil (FO) (15%Amylose/Soy/FO) was highly effective at preventing lung nodule formation in a nicotine-derived nitrosamine ketone (NNK)-induced lung cancer model. We asked herein whether adopting such a diet once cancers are established might also be beneficial. To test this, NNK-induced lung nodules were established in mice on a Western diet and the mice were then either kept on a Western diet or switched to various low CHO diets. Since we previously found that sedentary mice develop more lung nodules than active mice, we also compared the effect of exercise in this cancer progression model. We found that switching to a 15%Amylose/Soy/FO diet reduced lung nodules and slowed tumor growth with both 'active' and 'sedentary' mice. Ki67, cleaved caspase 3 and Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling assays suggested that the efficacy of the 15%Amylose/Soy/FO in lowering tumor nodule count and size was not due to a reduction in tumor cell proliferation, but to an increase in apoptosis. The 15%Amylose/Soy/FO diet also significantly lowered liver fatty acid synthase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 expression, pointing to a global metabolic switch from glycolysis to fatty acid oxidation. Mice fed the 15%Amylose/Soy/FO diet also had significantly reduced plasma levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor α. These results suggest that the 15%Amylose/Soy/FO diet may slow tumor growth by suppressing proinflammatory cytokines, inducing a metabolic switch away from glycolysis and inducing apoptosis in tumors.

The effect of diet and exercise on tobacco carcinogen-induced lung cancer.

In previous studies, we found that low-carbohydrate (CHO) diets reduced the incidence of tumors in mice genetically predisposed to cancer. However, because >90% of human cancers arise via carcinogen-induced somatic mutations, we investigated, herein, the role that different types and levels of CHO, protein and lipid play in lung cancer induced by the tobacco-specific carcinogen, nicotine-derived nitrosamine ketone (NNK) in A/J mice. We found lowering CHO levels significantly reduced lung nodules and blood glucose levels. We also found that soy protein was superior to casein and that coconut oil was ineffective at reducing lung nodules. Diets containing amylose or inulin (at 15% of total calories), soy protein (at 35%) and fat (at 50%, 30% being fish oil) were the most effective at reducing lung nodules. These fish oil-containing diets increased plasma levels of the ketone body, ß-hydroxybutyrate, while reducing both insulin and 8-isoprostane in plasma and bronchoalveolar interleukin-12 and lung PGE2 levels. After only 2 weeks on this diet, the levels of γ-H2AX were significantly reduced, 24 hours after NNK treatment. Housing these mice in two-tiered rat cages with exercise wheels led to similar mouse weights on the different diets, whereas keeping mice in standard mouse cages led to both significant weight differences between the low-CHO, soy protein, fish oil diet and Western diet and substantially more lung nodules than in the two-tiered cages. Our results suggest that low-CHO, soy protein, fish oil-containing diets, together with exercise, may reduce the incidence of lung cancer.

Acute drivers influence recent inshore Great Barrier Reef dynamics.

Understanding the dynamics of habitat-forming organisms is fundamental to managing natural ecosystems. Most studies of coral reef dynamics have focused on clear-water systems though corals inhabit many turbid regions. Here, we illustrate the key drivers of an inshore coral reef ecosystem using 10 years of biological, environmental, and disturbance data. Tropical cyclones, crown-of-thorns starfish, and coral bleaching are recognized as the major drivers of coral loss at mid- and offshore reefs along the Great Barrier Reef (GBR). In comparison, little is known about what drives temporal trends at inshore reefs closer to major anthropogenic stress. We assessed coral cover dynamics using state-space models within six major inshore GBR catchments. An overall decline was detected in nearly half (46%) of the 15 reefs at two depths (30 sites), while the rest exhibited fluctuating (23%), static (17%), or positive (13%) trends. Inshore reefs responded similarly to their offshore counterparts, where contemporary trends were predominantly influenced by acute disturbance events. Storms emerged as the major driver affecting the inshore GBR, with the effects of other drivers such as disease, juvenile coral density, and macroalgal and turf per cent cover varying from one catchment to another. Flooding was also associated with negative trends in live coral cover in two southern catchments, but the mechanism remains unclear as it is not reflected in available metrics of water quality and may act through indirect pathways.

UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells.

Herein we demonstrate that oncolytic herpes simplex virus-1 (HSV-1) potently activates human peripheral blood mononuclear cells (PBMCs) to lyse leukemic cell lines and primary acute myeloid leukemia samples, but not healthy allogeneic lymphocytes. Intriguingly, we found that UV light-inactivated HSV-1 (UV-HSV-1) is equally effective in promoting PBMC cytolysis of leukemic cells and is 1000- to 10 000-fold more potent at stimulating innate antileukemic responses than UV-inactivated cytomegalovirus, vesicular stomatitis virus, reovirus, or adenovirus. Mechanistically, UV-HSV-1 stimulates PBMC cytolysis of leukemic cells, partly via Toll-like receptor-2/protein kinase C/nuclear factor-κB signaling, and potently stimulates expression of CD69, degranulation, migration, and cytokine production in natural killer (NK) cells, suggesting that surface components of UV-HSV-1 directly activate NK cells. Importantly, UV-HSV-1 synergizes with interleukin-15 (IL-15) and IL-2 in inducing activation and cytolytic activity of NK cells. Additionally, UV-HSV-1 stimulates glycolysis and fatty acid oxidation-dependent oxygen consumption in NK cells, but only glycolysis is required for their enhanced antileukemic activity. Last, we demonstrate that T cell-depleted human PBMCs exposed to UV-HSV-1 provide a survival benefit in a murine xenograft model of human acute myeloid leukemia (AML). Taken together, our results support the preclinical development of UV-HSV-1 as an adjuvant, alone or in combination with IL-15, for allogeneic donor mononuclear cell infusions to treat AML.

A combined transgenic proteomic analysis and regulated trafficking of neuroligin-2.

Synapses, the basic units of communication in the brain, require complex molecular machinery for neurotransmitter release and reception. Whereas numerous components of excitatory postsynaptic sites have been identified, relatively few proteins are known that function at inhibitory postsynaptic sites. One such component is neuroligin-2 (NL2), an inhibitory synapse-specific cell surface protein that functions in cell adhesion and synaptic organization via binding to neurexins. In this study, we used a transgenic tandem affinity purification and mass spectrometry strategy to isolate and characterize NL2-associated complexes. Complexes purified from brains of transgenic His6-FLAG-YFP-NL2 mice showed enrichment in the Gene Ontology terms cell-cell signaling and synaptic transmission relative to complexes purified from wild type mice as a negative control. In addition to expected components including GABA receptor subunits and gephyrin, several novel proteins were isolated in association with NL2. Based on the presence of multiple components involved in trafficking and endocytosis, we showed that NL2 undergoes dynamin-dependent endocytosis in response to soluble ligand and colocalizes with VPS35 retromer in endosomes. Inhibitory synapses in brain also present a particular challenge for imaging. Whereas excitatory synapses on spines can be imaged with a fluorescent cell fill, inhibitory synapses require a molecular tag. We find the His6-FLAG-YFP-NL2 to be a suitable tag, with the unamplified YFP signal localizing appropriately to inhibitory synapses in multiple brain regions including cortex, hippocampus, thalamus, and basal ganglia. Altogether, we characterize NL2-associated complexes, demonstrate regulated trafficking of NL2, and provide tools for further proteomic and imaging studies of inhibitory synapses.

The role of SHIP in the development and activation of mouse mucosal and connective tissue mast cells.

Although SHIP is a well-established suppressor of IgE plus Ag-induced degranulation and cytokine production in bone marrow-derived mast cells (BMMCs), little is known about its role in connective tissue (CTMCs) or mucosal (MMCs) mast cells. In this study, we compared SHIP's role in the development as well as the IgE plus Ag and TLR-induced activation of CTMCs, MMCs, and BMMCs and found that SHIP delays the maturation of all three mast cell subsets and, surprisingly, that it is a positive regulator of IgE-induced BMMC survival. We also found that SHIP represses IgE plus Ag-induced degranulation of all three mast cell subsets and that TLR agonists do not trigger their degranulation, whether SHIP is present or not, nor do they enhance IgE plus Ag-induced degranulation. In terms of cytokine production, we found that in MMCs and BMMCs, which are poor producers of TLR-induced cytokines, SHIP is a potent negative regulator of IgE plus Ag-induced IL-6 and TNF-α production. Surprisingly, however, in splenic or peritoneal derived CTMCs, which are poor producers of IgE plus Ag-induced cytokines, SHIP is a potent positive regulator of TLR-induced cytokine production. Lastly, cell signaling and cytokine production studies with and without LY294002, wortmannin, and PI3Kα inhibitor-2, as well as with PI3K p85α(-/-) BMMCs and CTMCs, are consistent with SHIP positively regulating TLR-induced cytokine production via an adaptor-mediated pathway while negatively regulating IgE plus Ag-induced cytokine production by repressing the PI3K pathway.

Assessment of risk of bias in translational science.

Risk of bias in translational medicine may take one of three forms: A. a systematic error of methodology as it pertains to measurement or sampling (e.g., selection bias), B. a systematic defect of design that leads to estimates of experimental and control groups, and of effect sizes that substantially deviate from true values (e.g., information bias), and C. a systematic distortion of the analytical process, which results in a misrepresentation of the data with consequential errors of inference (e.g., inferential bias). Risk of bias can seriously adulterate the internal and the external validity of a clinical study, and, unless it is identified and systematically evaluated, can seriously hamper the process of comparative effectiveness and efficacy research and analysis for practice. The Cochrane Group and the Agency for Healthcare Research and Quality have independently developed instruments for assessing the meta-construct of risk of bias. The present article begins to discuss this dialectic.

RDR1 and SGS3, components of RNA-mediated gene silencing, are required for the regulation of cuticular wax biosynthesis in developing inflorescence stems of Arabidopsis.

The cuticle is a protective layer that coats the primary aerial surfaces of land plants and mediates plant interactions with the environment. It is synthesized by epidermal cells and is composed of a cutin polyester matrix that is embedded and covered with cuticular waxes. Recently, we have discovered a novel regulatory mechanism of cuticular wax biosynthesis that involves the ECERIFERUM7 (CER7) ribonuclease, a core subunit of the exosome. We hypothesized that at the onset of wax production, the CER7 ribonuclease degrades an mRNA specifying a repressor of CER3, a wax biosynthetic gene whose protein product is required for wax formation via the decarbonylation pathway. In the absence of this repressor, CER3 is expressed, leading to wax production. To identify the putative repressor of CER3 and to unravel the mechanism of CER7-mediated regulation of wax production, we performed a screen for suppressors of the cer7 mutant. Our screen resulted in the isolation of components of the RNA-silencing machinery, RNA-DEPENDENT RNA POLYMERASE1 and SUPPRESSOR OF GENE SILENCING3, implicating RNA silencing in the control of cuticular wax deposition during inflorescence stem development in Arabidopsis (Arabidopsis thaliana).

SHIP represses Th2 skewing by inhibiting IL-4 production from basophils.

We report that SHIP(-/-) mice, compared to SHIP(+/+) mice, are Th2 skewed with elevated serum IgE and twice as many splenic CD4(+) Th2 cells that, when stimulated with anti-CD3, produce more IL-4 and less IFN-γ. Exploring the reason for this Th2 skewing, we found that freshly isolated SHIP(-/-) splenic and bone marrow basophils are present in elevated numbers and secrete far more IL-4 in response to IL-3 or to FcεRI stimulation than do WT basophils. These SHIP(-/-) basophils markedly skew wild-type macrophage colony stimulating factor-derived macrophages toward an M2 phenotype, stimulate OT-II CD4(+) Th cells to differentiate into Th2 cells, and trigger SHIP(+/+) B cells to become IgE-producing cells. All these effects are completely abrogated with neutralizing anti-IL-4 Ab. Exploring the cell signaling pathways responsible for hyperproduction of IL-4 by SHIP(-/-) basophils, we found that IL-3-induced activation of the PI3K pathway is significantly enhanced and that PI3K inhibitors, especially a p110α inhibitor, dramatically suppresses IL-4 production from these cells. In vivo studies, in which basophils were depleted from mast cell-deficient SHIP(+/+) and SHIP(-/-) mice, confirmed the central role that basophils play in the Th2 skewing of naive SHIP-deficient mice. Taken together, these studies demonstrate that SHIP is a potent negative regulator of IL-4 production from basophils and thus may be a novel therapeutic target for Th1- and Th2-related diseases.

Management of Coronavirus Disease-2019 Infection in Pregnancy.

Although the majority of pregnant patients who contract severe acute respiratory syndrome coronavirus 2 will have a mild course of illness, pregnant patients with coronavirus disease-2019 are more likely than their nonpregnant counterparts to develop a severe illness with an increased risk of poor maternal and fetal outcomes. Although the extent of research in this specific patient population remains limited, there are tenets of care with which physicians and other providers must be familiar to increase the chances of better outcomes for the two patients in their care.

Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice.

As more groups investigate the role of myeloid-derived suppressor cells (MDSCs) in promoting the growth of primary tumors and distant tumor metastases, it is imperative to ensure the accurate detection and quantification of MDSC immunosuppression ex vivo. MDSCs are defined by their ability to suppress immune responses. Although different in vitro culture conditions have been used to study MDSCs, the effect of different culture conditions on MDSC immunosuppression is unknown. We therefore isolated MDSCs from the lungs and spleens of 4T1 murine mammary tumor-bearing mice and assayed MDSC-mediated suppression of T cell responses under different culture conditions. We found that 4T1-induced MDSCs effectively suppressed T cell proliferation under serum-free conditions, but not when fetal calf serum (FCS) was present. FCS neither altered the immunosuppressive activities of other myeloid cell types (i.e., peritoneal or tumor-associated macrophages) nor modified the susceptibility of T cells to myeloid cell-mediated suppression, but instead acted directly on 4T1-induced MDSCs to significantly reduce their immunosuppressive function. Importantly, we found that bovine serum albumin was a major contributor to the antagonistic effects of FCS on 4T1-induced MDSC immunosuppression by inhibiting reactive oxygen species production from MDSCs. This work reveals that in vitro culture conditions influence the immunosuppressive properties of MDSCs and highlights the importance of testing different culture conditions on MDSC phenotype to ensure that MDSC immunosuppression is not being masked. These data have important implications for the accurate detection and identification of MDSCs, as well as for determining the influence of MDSC-mediated immunosuppression on primary and metastatic tumor growth.

"You have to be sure that the patient has the full picture": Adaptation of the Best Case/Worst Case communication tool for geriatric oncology.

BACKGROUND: Shared decision making (SDM) is especially important for older adults with cancer given the risks of over- and undertreatment, uncertainty regarding benefits/harms worsened by research underrepresentation, and individual preferences. We aimed to adapt the Best Case/Worst Case (BC/WC) communication tool, which improves SDM in geriatric surgery, to geriatric oncology. METHODS: We conducted focus groups with 40 stakeholders (fourteen older adults with lung cancer, twelve caregivers, fourteen medical oncologists) to elicit perspectives on using the BC/WC tool for geriatric oncology and to identify components needing refinement. During each focus group, participants viewed a BC/WC demonstration video and answered questions modified from the Decision Aid Acceptability Scale. We analyzed transcripts using deductive and inductive thematic analyses. DISCUSSION: Participants believed that the BC/WC tool could help patients understand their cancer care choices, explore tradeoffs and picture potential outcomes, and deliberate about decisions based on their goals, preferences, and values. Oncologists also reported the tool could guide conversations to address points that may frequently be skipped (e.g., alternative options, treatment goals). Participant preferences varied widely regarding discussion of the worst-case scenario and desire for statistical information. CONCLUSION: The BC/WC tool is a promising strategy that may improve SDM in geriatric oncology and patient understanding of alternative options and treatment goals. Based on participant input, adaptations will include framing cancer care as a series of decisions, eliciting patient preferences and asking permission before offering the worst-case scenario, and selection of the two most relevant options to present if multiple exist.

CCL5 production in lung cancer cells leads to an altered immune microenvironment and promotes tumor development.

Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumor-derived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRASG12V or EGFRL858R expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (Tregs), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high CCL5 expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.

Changes in older adults' life space during lung cancer treatment: A mixed methods cohort study.

BACKGROUND: Maintenance of function during cancer treatment is important to older adults. Characteristics associated with pretreatment life-space mobility and changes during non-small cell lung cancer (NSCLC) treatment remain unknown. METHODS: This mixed methods cohort study recruited adults age ≥65 with advanced NSCLC starting palliative chemotherapy, immunotherapy, and/or targeted therapy from a Comprehensive Cancer Center, Veterans Affairs, and safety-net clinic. Patients completed geriatric assessments including Life-Space Assessment (LSA) pretreatment and at 1, 2, 4, and 6 months after treatment initiation. LSA scores range from 0 to 120 (greater mobility); LSA <60 is considered restricted. We used mixed-effects models to examine pretreatment LSA, change from 0 to 1 month, and change from 1 to 6 months. A subgroup participated in semistructured interviews pretreatment and at 2 and 6 months to understand the patient experience of life-space change. For each interview participant, we created joint displays of longitudinal LSA scores juxtaposed with illustrative quotes. RESULTS: Among 93 patients, median age was 73 (range 65-94). Mean pretreatment LSA score was 67.1. On average, LSA declined 10.1 points from pretreatment to 1 month and remained stable at 6 months. Pretreatment LSA score was associated with several demographic, clinical, geriatric assessment, and symptom characteristics. LSA decline at 1 month was greater among patients with high anxiety (slope = -12.6 vs. -2.3, p = 0.048). Pretreatment body mass index <21 kg/m2 was associated with LSA improvement from 1 to 6 months (slope = 4.1 vs. -0.04, p = 0.003). Joint displays illustrated the impact of different life-space trajectories on patients' lives in their words. CONCLUSION: Older adults with NSCLC have low pretreatment life space with many developing restricted life space during treatment. Incorporating life-space assessments into clinical cancer care may help older adults concretely visualize how treatment might impact their daily function to allow for informed decision making and identify early changes in mobility to implement supportive interventions.

Immune-Related Endocrine Dysfunctions in Combined Modalities of Treatment: Real-World Data.

The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) in cancer management. A retrospective analysis was conducted on consecutive patients ≥18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a university hospital in Hong Kong. Patients were reviewed up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis. A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) were included. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo + ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted + ICI). A significantly higher proportion of patients using targeted + ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (≥65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. This large, real-world cohort demonstrates that targeted + ICI has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is essential in older populations.

IgE-induced mast cell survival requires the prolonged generation of reactive oxygen species.

We show in this study that the ability of five different monomeric IgEs to enhance murine bone marrow-derived mast cell (BMMC) survival correlates with their ability to stimulate extracellular calcium (Ca(2+)) entry. However, whereas IgE+Ag more potently stimulates Ca(2+) entry, it does not enhance survival under our conditions. Exploring this further, we found that whereas all five monomeric IgEs stimulate a less robust Ca(2+) entry than IgE+Ag initially, they all trigger a more prolonged Ca(2+) influx, generation of reactive oxygen species (ROS), and ERK phosphorylation. These prolonged signaling events correlate with their survival-enhancing ability and positively feedback on each other to generate the prosurvival cytokine, IL-3. Interestingly, the prolonged ERK phosphorylation induced by IgE appears to be regulated by a MAPK phosphatase rather than MEK. IgE-induced ROS generation, unlike that triggered by IgE+Ag, is not mediated by 5-lipoxygenase. Moreover, ROS inhibitors, which block both IgE-induced ROS production and Ca(2+) influx, convert the prolonged ERK phosphorylation induced by IgE into the abbreviated phosphorylation pattern observed with IgE+Ag and prevent IL-3 generation. In support of the essential role that IgE-induced ROS plays in IgE-enhanced BMMC survival, we found the addition of H(2)O(2) to IgE+Ag-stimulated BMMCs leads to IL-3 secretion.

Updates in Cardiac Arrest Resuscitation.

There are approximately 350,000 out-of-hospital cardiac arrests and 200,000 in-hospital cardiac arrests annually in the United States, with survival rates of approximately 5% to 10% and 24%, respectively. The critical factors that have an impact on cardiac arrest survival include prompt recognition and activation of prehospital care, early cardiopulmonary resuscitation, and rapid defibrillation. Advanced life support protocols are continually refined to optimize intracardiac arrest management and improve survival with favorable neurologic outcome. This article focuses on current treatment recommendations for adult nontraumatic cardiac arrest, with emphasis on the latest evidence and controversies regarding intracardiac arrest management.