Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma.

BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/- MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20-74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8-36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma samples. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.

Ecology of mycorrhizae: a conceptual framework for complex interactions among plants and fungi.

Mycorrhizae regulate elemental and energy flows in terrestrial ecosystems. We understand much of how mycorrhizae work, but integrating all possible mechanisms into a whole has proven elusive. Multiple evolutionary events and the long evolutionary history mean that different plants and fungi bring independent characteristics to the symbiosis. This variety results in extensive physiological variation. How do we integrate functional responses with diversity to understand the role of mycorrhizae in ecosystems? We review ecophysiological mechanisms of mycorrhizae and organize these into functional groups. Species-area relationships are not curvilinear, but resemble the "broken stick" model. We coupled functional groups with a metacommunity analysis to show how complex behavior can be generated using a simple matrix model of resource exchange. This approach provides insights into how we might integrate diversity and function across landscapes.

The molecular genetic characterization of the 'Bobwhite' bread wheat family using AFLPs and the effect of the T1BL.1RS translocation.

Bobwhite is a generic name that refers to all sister lines derived from the cross CM 33203 with the pedigree Aurora//Kalyan/Bluebird/3/Woodpecker made by the CIMMYT bread wheat program in the early 1970s. Individual sister lines can be distinguished by their unique selection history. One of the parents, Aurora, contains the T1BL.1RS translocation from rye, and approximately 85% of the sister lines have inherited the translocation. The sister lines demonstrate great variability for agronomic traits such as maturity, height, grain color, reaction to leaf rust, stem rust, yellow rust, septoria leaf blotch and powdery mildew. Certain groups of sister lines derived from particular F(1) plants can be distinguished by their phenotype. One hundred and one Bobwhite sister lines were fingerprinted using four AFLP enzyme/primer combinations. Following multivariate analysis, two main and very distinct clusters were found, which reflected the presence or absence of the T1BL.1RS translocation. Within these clusters, lines clustered together, for the most part, with other sister lines sharing a common selection history. Removal of the AFLP markers that were correlated with the presence or absence of the translocation caused lines to cluster based on pedigree alone. Therefore, the presence of translocations in wheat could bias genetic diversity studies using unmapped markers such as AFLPs that are located on the translocated segment(s), with the result that the resulting clusters will not reflect the true degree of relatedness.

Reconstruction of the historical changes in mycorrhizal fungal communities under anthropogenic nitrogen deposition.

Archived soil samples (1937-1999) and historic air quality data from the Los Angeles Basin were used for reconstructing the record of change between atmospheric NO(x) loads, soil delta(15)N values and the diversity of arbuscular mycorrhizae (AM), which are ubiquitous plant-fungus mutualists that control plant community productivity. A tripling of atmospheric NO(x) loads between 1937 and the 1970s was paralleled by soil nitrogen enrichment (delta(15)N = 3.18). From 1975 onwards, atmospheric NO(x) declined, but soils became nitrogen saturated (delta(15) N = -4 and NO(3)-nitrogen = 171mgkg(-1)). The shifts in the AM community followed 28 years of atmospheric nitrogen enrichment and coincided with the onset of soil nitrogen saturation. Such changes were manifest in the loss of AM productivity, species richness (one species per year), three genera (Acaulospora, Scutellospora and Gigaspora) in the spore community and Gigaspora within the roots. Nitrogen enrichment also enhanced the proliferation of potentially less mutualistic species of Glomus. Autoregressive models implied that such patterns will persist and be driven by soil nitrogen cycling patterns. Chronic nitrogen enrichment from air pollution thus alters the diversity and mutualistic functioning of AM communities, which, in turn, may influence the plant community.

How injection drug users coped with testing HIV-seropositive: implications for subsequent health-related behaviors.

At entry into methadone maintenance treatment, 94 HIV-positive injection drug users (IDUs) completed the Coping Reponses Inventory, which asked them to "describe your feelings and experiences when you first learned you were HIV positive." Controlling for time since HIV testing, a reliance on avoidance coping following HIV testing was correlated with high levels of recent HIV risk behavior and poor health at entry into the study. The use of any coping strategy, particularly approach strategies, was related to medication adherence. Hierarchical regression analysis showed that avoidance coping accounted for a significant proportion of the variance in recent HIV risk behavior over and above that accounted for by the other variables. Other independent predictors of continued risk behavior were poor health, lack of social support, and low levels of HIV/AIDS knowledge. The need for interventions to help injection drug users (IDUs) cope subsequent to testing HIV seropositive is discussed.

Spiritual and religious support in recovery from addiction among HIV-positive injection drug users.

The current study examined the association between support and comfort derived from religion or spirituality and abstinence from illicit drugs in a sample of 43 HIV-positive injection drug users entering a methadone maintenance program. Patients with high ratings of perceived spiritual or religious support were abstinent from illicit drugs significantly longer during the first six months of methadone maintenance than were patients with lower ratings. Controlling for the influence of pretreatment variables (addiction and psychiatric severity, CD4 count, social support, and optimism), and during-treatment variables (methadone dose and attendance at counseling sessions), hierarchical regression analysis showed that strength of religious and spiritual support was a significant independent predictor of abstinence. These findings suggest that spirituality may be an important dimension of patient experience to assess in future addiction treatment outcome research.

Predictors of nonadherence to HIV-related medication regimens during methadone stabilization.

Nonadherence to HIV-related medication regimens among drug-abusing patients decreases therapeutic effectiveness and may limit patient access to newer, highly active antiretroviral therapies (HAART). A number of factors have been associated with medication nonadherence; however, few studies have examined predictors of nonadherence specifically in HIV-positive drug abusers. In the current study, a comprehensive assessment battery was administered to 42 HIV-positive, injection drug users beginning methadone maintenance. HIV-related medication adherence was assessed weekly by self-report during the 4-week methadone stabilization phase. Thirty-six percent of patients reported less than 80% adherence to their medication regimen at entry into methadone. Medication adherence increased significantly during the 4-week stabilization phase. Significant zero-order correlations were found between nonadherence during stabilization and viral load, low educational attainment, depression, and neuropsychological tests of problem solving ability and cognitive flexibility. Independent predictors of nonadherence were low levels of education and poor emotional functioning. Implications for early intervention are discussed.

Isolation and structural identification of a germination inhibitor in fire-recruiters from the California chaparral.

A role for inhibitors as regulators of seed dormancy in fire-dependent annuals and their nondormant (fire-independent) congeners was examined in the family Hydrophyllaceae. From seeds of the fire-dependent species, Emmenanthe penduliflora, Phacelia minor, P. brachyloba, and P. grandiflora, extracts were obtained that were found to be largely self-inhibitory and potent inhibitors of seed germination in nondormant congeners. Lower activity was detected in the fire-independent species, P. tanacetifolia and P. campanularia. The inhibitory activity was associated with the new sucrose ester, 6-O-linoleyl-alpha-D-glucopyranosyl-beta-D-fructofuranoside.

Identification of a 41 kDa protein embedded in the biosilica of scales and bristles isolated from Mallomonas splendens (Synurophyceae, Ochrophyta).

Cells of the photosynthetic protist Mallomonas splendens (Synurophyceae, Ochrophyta) are encased within a highly patterned wall or scale case that consists of silicified scales and bristles. In an effort to understand the mechanisms that unicellular protists utilize to produce elaborate, mineralized structures of great complexity and hierarchical structure, we identified and characterized a 41 kDa protein from purified scales/bristles isolated from M. splendens (SP41 for Scale Protein of 41 kDa). A cDNA encoding this protein was isolated and sequence analysis indicated that it is a novel protein. Polyclonal antibodies were generated against bacterially expressed SP41 and used to localize the protein throughout scale and bristle morphogenesis. Immunoelectron microscopy confirmed the biochemical data that SP41 is a component of mature scales and bristles, the protein localizing to silicified components of the purified extracellular matrix. During scale and bristle biogenesis within the cell, SP41 is deposited into a specialized Silica Deposition Vesicle (SDV) concomitant with silica deposition, a highly regulated event during scale and bristle formation. These results argue for SP41 playing a role in morphogenesis and/or silicification within the SDV during scale and bristle biogenesis.

Endo- and ectomycorrhizas in Quercus agrifolia Nee. (Fagaceae): patterns of root colonization and effects on seedling growth.

We documented the patterns of root occupancy by Glomalean and ectomycorrhizal (EM) fungi in Quercus agrifolia, and host plant responses to inoculation with each mycorrhizal type alone or in combination. Glomalean hyphae, coils and vesicles, and EM root tips were recorded. Colonization patterns conformed to a succession from Glomalean and EM fungi in 1-year-old seedlings to predominantly EM in saplings (>11 years old); both mycorrhizal types were rarely detected within the same root segment. Inoculation of Q. agrifolia seedlings with EM or Glomalean fungi (AM) alone or in combination (EM+AM) altered the cost:benefit relationship of mycorrhizas to the host plant. Seedling survival, plant biomass, foliar nitrogen (N), and phosphorus (P) status were greatest in EM- or AM-only inoculated seedlings. Seedlings inoculated with both mycorrhizal types (AM+EM) exhibited the lowest survival rates, biomass, foliar N, and P levels. Roots of these plants were highly colonized by both EM (38% root length colonized) and Glomalean fungi (34%). Because these levels of colonization were similar to those detected in 1-year-old field seedlings, the presence of both mycorrhizal types may be a carbon cost and, in turn, less beneficial to oaks during establishment in the field. However, the shift to EM colonization in older plants suggests that mycorrhizal effects may become positive with time.

Graduated elastic compression stockings on a stroke unit: a feasibility study.

BACKGROUND: thrombo-embolic complications are important causes of morbidity and mortality after acute stroke. Anticoagulant prophylaxis is contraindicated in intracerebral haemorrhage and not recommended in acute ischaemic stroke because of increased risk of cerebral haemorrhage. Graduated elastic compression stockings are a simple alternative but are not widely used in stroke patients, perhaps because of perceived contraindications and problems with tolerability. OBJECTIVES: to establish the feasibility and tolerability of graduated compression stockings on a stroke unit. DESIGN: we assessed 112 consecutive stroke patients for contraindications to and tolerability of graduated compression stockings. MEASUREMENTS: we used clinical indices and ankle-brachial Doppler pressure measures to assess suitability. We prospectively assessed tolerability of the stockings. RESULTS: Ninety-four (84%) of the 112 patients had no contraindications to the use of the stockings. The most common contraindication was an ankle-brachial index of <0.8. Other contraindications were marked dependent leg oedema (1/18) and severe venous ulceration. Eighty-nine (95%) of the 94 patients tolerated the stockings and wore them until discharge. Skin irritation was the most common reason for intolerance. CONCLUSIONS: contraindications to the use of graduated compression stockings can be defined using clinical criteria and a Doppler machine to calculate an ankle-brachial pressure index. If this is done, tolerability is excellent. This approach may be a useful alternative in preventing venous thrombo-embolism in stroke patients.

The influence of coping and depression on abstinence from illicit drug use in methadone-maintained patients.

Use of illicit drugs by opioid-dependent patients maintained on methadone undermines the benefits of methadone maintenance treatment. Because supplemental pharmacologic approaches have met with limited success, it is important to identify psychological mechanisms associated with drug use that potentially could contribute to the development of more effective treatments. To investigate this issue, the current study assessed coping and depression in 307 methadone-maintained patients and found a reliance on avoidant coping strategies, most notably by depressed patients. Patients who achieved abstinence following a 12-week coping skills training intervention decreased the use of avoidant coping strategies. Drug use at the 6-month follow-up was related to gains made during treatment, specifically reduced cognitive avoidance, reduced depression, and number of drug-free weeks during treatment.

Continuation of high-risk behavior by HIV-positive drug users. Treatment implications.

Drug users who are positive for the human immunodeficiency virus (HIV) represent a major vector of HIV transmission, yet relatively little is known about their continued drug- and sex-related HIV-risk behavior, which may impede the development of effective risk-reduction interventions. In this study, 50 HIV-seropositive injection drug users entering methadone maintenance treatment completed a comprehensive risk assessment battery, including self-report of HIV-risk behavior since learning HIV serostatus, and measures of risk-reduction information, motivation, and behavioral skills. We found that a disconcertingly high proportion of patients (66%) reported having engaged in HIV-risk behavior since learning their HIV-seropositive status. Level of HIV-related knowledge did not predict high-risk behavior. Drug-related risk behavior was predicted by psychiatric severity and poor behavioral skills. Sex-related risk was predicted by low levels of motivation and poor behavioral skills. Implications of these findings for treatment are discussed.

Levels of mineral nutrients in fresh- and frozen bulk hydrated biological specimens: a comparison of EDS data collected in the environmental SEM and a conventional cryo-SEM.

Energy-dispersive X-ray microanalysis (EDS) was compared in fresh- and frozen bulk hydrated tissues using the Environmental SEM (ESEM) and conventional cryo-SEM, respectively. Analysis of globoid inclusions of Eucalyptus calophylla seed from two soil types demonstrated that higher levels of cations (K, Ca, Mg, Al, Fe, Mn, Cu, Zn) occurred in seeds from soils containing higher levels of Al, while EDS-detectable levels of S and P were dependent upon the techniques utilised. Cumulative changes in ESEM-EDS-detectable levels of S and P were characterized by collecting cumulative spectra from nutrient standards and compared with those for K. Progressive increases in K occurred and were consistent with an enriching effect. Levels of S and P increased during early analysis (40-60 sec live time) and decreased thereafter. The semi-conductive nature of biological samples, the loss of anions and gain of cations from the net negatively-charged electron interaction volume contributed to an electrochemical bias. These local modifications in fluid chemistry were reversible. Dehydration effects also occurred in stable, 'wet' samples. These differences indicated that EDS in ESEM may be limited to cations rather than anions, and that changes in fluid electrochemistry and dehydration may affect the level and distribution of elements.

Microanalytical studies of metal localization in biological tissues by environmental SEM.

The presence and distribution of Al and Mn in floral and seed tissues of eucalypts from Al-contaminated soils was analyzed using energy-dispersive X-ray microanalysis (EDS) in an environmental scanning electron microscope (ESEM). EDS by ESEM determined the distribution of elements between tissue types was suitable for intact samples or those with lower available moisture or intact specimens. The analytical technique was not appropriate for highly vascular samples. Other factors influencing the detection of elements by ESEM-EDS were electron scattering and the relative concentration and localization of elements within the tissues. EDS-detectable levels were significantly correlated with tissue concentrations determined by atomic absorption spectrophotometry for Mn but not for Al.