Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the ...oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non-small cell lung cancer.
Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens.
Thirty-three patients were treated (13 in phase I, 20 in phase Ib). In phase I, both ICI-naïve and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLT). No DLTs were observed, and the recommended phase I dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of six ICI-naïve and 24 ICI-pretreated patients evaluable for response, four (13%) had partial response two confirmed, one unconfirmed with subsequent prolonged stable disease (SD), one unconfirmed with subsequent progressive disease (PD), 16 (53%) had SD, and 10 (33%) had PD for a DCR of 67%. In the ICI-pretreated cohort, three patients (one confirmed, two unconfirmed) had partial response and 10 had SD. Pretreatment CD8
T-cell presence in tumor stromal regions was associated with treatment benefit.
Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment.
The mushroom agroindustry generates a huge amount of waste from mushroom production (WMP). The composition of WMP is not standardized but differs mainly in terms of organic matter (OM) content and OM ...biodegradability. This makes WMP management, including anaerobic digestion (AD), a significant challenge. A potential solution could be co-digestion of WMP with municipal sewage sludge (SS), especially SS generated in small rural wastewater treatment plants (WWTPs). Therefore, this study investigated mesophilic methane production (MP) from WMP, SS, and mixtures of SS and WMP at ratios of 70:30, 50:50, and 30:70 (w/w OM). Even though the maximum cumulative MP from WMP was relatively low (approx. 60 NL/kg OM), co-digesting WMP with SS increased both MP and the methane content of the biogas: with 30%, 50%, and 70% shares of SS, MP increased almost 2, 2.5, and 3.3 times, and the methane content increased to 61%, 62%, and 64%, respectively. As the SS content was increased, the kinetic coefficients of MP and OM removal decreased (from 0.211 to 0.146 d−1 and from 0.215 to 0.152 d−1), whereas the initial rate of MP and of OM removal increased (from 12.5 to 36.8 NL/(kg OM·d) and from 0.51 kg OM/(m3·d) to 0.59 kg OM/(m3·d), respectively). The effectiveness of OM removal (EOMrem) was lowest with WMP only, at 46.6%. When the SS content of the mixtures was increased to 30%, 50%, and 70%, EOMrem also increased to 55.3%, 60.1%, and 64.9%, respectively. The relationship between maximal MP and the overall OM removed was such that both increased simultaneously. The higher values of EOMrem and, consequently, the lower final contents of OM with more effective MP indicate that the organics were degraded more efficiently. These results suggest that co-digestion may be a profitable solution for simultaneously utilizing both of these waste products, increasing the efficiency of biogas production to such an extent that it would be profitable to conduct AD on mushroom farms. This is a flexible approach that allows varying proportions of WMP and SS to be used, depending on the availability of both substrates and the energy needs of the mushroom farm. However, it should be borne in mind that a higher share of WMP results in lower gas productivity.
Seasonally fluctuating water levels, known as ‘flood pulses’, control the productivity of large river fisheries, but the extent and mechanisms through which flood pulses affect fishery yields are ...poorly understood. To quantify and better understand flood pulse effects on fishery yields, this study applied regression techniques to a hydrological and fishery record (years 1993–2004) for 42 species of the Amazon River floodplains. Models based on indices of fishing effort, high waters and low waters explained most of the interannual variability in yields (R2=0.8). The results indicated that high and low waters in any given year affected fishery yields two and three years later through changes in fish biomass available for harvesting, contributing 18% of the explained variability in yields. Fishing effort appeared to amplify high and low water effects by changing in direct proportion to changes in fish biomass available for harvesting, contributing 62% of the explained variability in yields. Although high waters are generally expected to have greater relative influence on fishery yields than low waters, high and low waters exerted equal forcing on these Amazonian river-floodplain fishery yields. These findings highlight the complex dynamics of river-floodplain fisheries in relation to interannual variability in flood pulses.
Melanoma cells have the ability to switch to a dedifferentiated, invasive phenotype in response to multiple stimuli. Here, we show that exposure of melanomas to multiple stresses including BRAF-MEK ...inhibitor therapy, hypoxia, and UV irradiation leads to an increase in histone deacetylase 8 (HDAC8) activity and the adoption of a drug-resistant phenotype. Mass spectrometry-based phosphoproteomics implicated HDAC8 in the regulation of MAPK and AP-1 signaling. Introduction of HDAC8 into drug-naïve melanoma cells conveyed resistance both
and
. HDAC8-mediated BRAF inhibitor resistance was mediated via receptor tyrosine kinase activation, leading to MAPK signaling. Although HDACs function at the histone level, they also regulate nonhistone substrates, and introduction of HDAC8 decreased the acetylation of c-Jun, increasing its transcriptional activity and enriching for an AP-1 gene signature. Mutation of the putative c-Jun acetylation site at lysine 273 increased transcriptional activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition.
xenograft studies confirmed the key role of HDAC8 in therapeutic adaptation, with both nonselective and HDAC8-specific inhibitors enhancing the durability of BRAF inhibitor therapy. Our studies demonstrate that HDAC8-specific inhibitors limit the adaptation of melanoma cells to multiple stresses including BRAF-MEK inhibition. SIGNIFICANCE: This study provides evidence that HDAC8 drives transcriptional plasticity in melanoma cells in response to a range of stresses through direct deacetylation of c-Jun.
http://cancerres.aacrjournals.org/content/canres/79/11/2947/F1.large.jpg.
Tunafasi is a community-based rehabilitation (CBR) programme for persons with disability, implemented by a local non-governmental organisation in Uvira, Democratic Republic of Congo, in partnership ...with government. To assess affordability and support discussions with the government about continued financing and implementation, Tunafasi representatives commissioned a cost-effectiveness study of the programme's health component.
This study aimed to estimate the programme's impacts, costs, cost per disability-adjusted life year (DALY) averted and affordability of the health component implemented from February 2019 to December 2021.
Health-related improvements were assessed for a sample of 511 persons with disability and converted to DALYs averted. Total expenditure during the period February 2019 to December 2021 was estimated from audited financial statements. The cost per DALY averted was estimated by dividing total programme expenditure by the sum of DALYs averted and compared against newly generated, country-specific thresholds to assess affordability.
The programme cost $55 729.00 to implement from February 2019 to December 2021 and averted 234 DALYs in 511 persons, at a cost per DALY averted of $224.00. This falls above the affordability threshold of $54.00 - $199.00.
While the cost per DALY averted is higher than what thresholds consider affordable for Democratic Republic of Congo, improved engagement from CBR facilitators and greater possibilities for treatment in the post-pandemic era should improve results.
This new CBR implementation modality offers a possibly affordable solution to African governments struggling to operationalise disability commitments such as United Nations Convention on the Rights of Persons with Disabilities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. Here, we integrate DNA copy number, somatic mutations, RNA-sequencing, and expression ...proteomics in a cohort of 108 squamous cell lung cancer (SCC) patients. We identify three proteomic subtypes, two of which (Inflamed, Redox) comprise 87% of tumors. The Inflamed subtype is enriched with neutrophils, B-cells, and monocytes and expresses more PD-1. Redox tumours are enriched for oxidation-reduction and glutathione pathways and harbor more NFE2L2/KEAP1 alterations and copy gain in the 3q2 locus. Proteomic subtypes are not associated with patient survival. However, B-cell-rich tertiary lymph node structures, more common in Inflamed, are associated with better survival. We identify metabolic vulnerabilities (TP63, PSAT1, and TFRC) in Redox. Our work provides a powerful resource for lung SCC biology and suggests therapeutic opportunities based on redox metabolism and immune cell infiltrates.
New technologies, such as multiplex immunofluorescence microscopy (mIF), are being developed and used for the assessment and visualization of the tumor immune microenvironment (TIME). These assays ...produce not only an estimate of the abundance of immune cells in the TIME, but also their spatial locations. However, there are currently few approaches to analyze the spatial context of the TIME. Therefore, we have developed a framework for the spatial analysis of the TIME using Ripley's K, coupled with a permutation-based framework to estimate and measure the departure from complete spatial randomness (CSR) as a measure of the interactions between immune cells. This approach was then applied to epithelial ovarian cancer (EOC) using mIF collected on intra-tumoral regions of interest (ROIs) and tissue microarrays (TMAs) from 160 high-grade serous ovarian carcinoma patients in the African American Cancer Epidemiology Study (AACES) (94 subjects on TMAs resulting in 263 tissue cores; 93 subjects with 260 ROIs; 27 subjects with both TMA and ROI data). Cox proportional hazard models were constructed to determine the association of abundance and spatial clustering of tumor-infiltrating lymphocytes (CD3+), cytotoxic T-cells (CD8+CD3+), and regulatory T-cells (CD3+FoxP3+) with overall survival. Analysis was done on TMA and ROIs, treating the TMA data as validation of the findings from the ROIs. We found that EOC patients with high abundance and low spatial clustering of tumor-infiltrating lymphocytes and T-cell subsets in their tumors had the best overall survival. Additionally, patients with EOC tumors displaying high co-occurrence of cytotoxic T-cells and regulatory T-cells had the best overall survival. Grouping women with ovarian cancer based on both cell abundance and spatial contexture showed better discrimination for survival than grouping ovarian cancer cases only by cell abundance. These findings underscore the prognostic importance of evaluating not only immune cell abundance but also the spatial contexture of the immune cells in the TIME. In conclusion, the application of this spatial analysis framework to the study of the TIME could lead to the identification of immune content and spatial architecture that could aid in the determination of patients that are likely to respond to immunotherapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Wilson disease (WD), a copper metabolism disorder, occurs due to the presence of mutations in the gene encoding ATP7B, a protein that primarily facilitates hepatic copper excretion. A better ...understanding of spectrum and functional significance of ATP7B variants is critical to formulating targeted and personalized therapies. Henceforth, we screened and sequenced 21 exons of ATP7B gene from 50 WD patients and 60 healthy subjects. We identified 28 variants comprising, seven novels in 20% alleles, while eight variations affecting 23% alleles were first time reported in Indian cohort. The c.813C>A, p.(Cys271*) (10%) was the most frequent mutation. Bioinformatics analysis revealed five of seven novel variants viz. c.1600C>A, p.(Pro534Thr); c.1616C>A, p.(Pro539His); c.1924G>T, p.(Asp642Tyr); c.2168G>C, p.(Arg723Thr); c.2174G>C, p.(Arg725Thr) resulted in protein misfolding. Sequence conservation analysis of ATP7B regions containing novel variants documented an evolutionarily conserved nature. Functional analysis of these novel variants in five different cell lines lacking inherent ATP7B expression demonstrated sensitivity to CuCl2‐treatment, experiencing augmented cellular copper retention and decreased copper excretion as well as ceruloplasmin secretion to that of wildtype‐ATP7B expressing cells. Interestingly, pharmacological chaperone 4‐phenylbutyrate, a clinically approved compound, partially restored protein function of ATP7B mutants. These findings might enable novel treatment strategies in WD by clinically enhancing the protein expression of mutant ATP7B with residual copper export activity.
Wilson disease exhibits clinical heterogeneity due to presence of various mutations in the ATP7B gene, leading to copper‐toxicity, rendering the available treatment procedure less effective and requires specific therapeutic alternatives. We report 21 mutations, of which, eight were never reported earlier in Indian population and seven are novel variants. Five novel variants resulted in functional decline of ATP7B due to protein misfolding. However, treatment with 4‐phenylbytyrate successfully restored partial ATP7B functions, thereby providing a therapeutic option for future consideration.
Rationale Recent studies have discovered several unique tumor response subgroups outside of response classification by Response Evaluation Criteria for Solid Tumors (RECIST), such as mixed response ...and oligometastasis. These subtypes have a distinctive property, lesion heterogeneity defined as diversity of tumor growth profiles in RECIST target lesions. Furthermore, many cancer clinical trials have been activated to evaluate various treatment options for heterogeneity-related subgroups (e.g., 29 trials so far listed in clinicaltrials.gov for cancer patients with oligometastasis). Some of the trials have shown survival benefit by tailored treatment strategies. This evidence presents the unmet need to incorporate lesion heterogeneity to improve RECIST response classification. Method An approach for Lesion Heterogeneity Classification (LeHeC) was developed using a contemporary statistical approach to assess target lesion variation, characterize patient treatment response, and translate informative evidence to improving treatment strategy. A mixed effect linear model was used to determine lesion heterogeneity. Further analysis was conducted to classify various types of lesion variation and incorporate with RECIST to enhance response classification. A study cohort of 110 target lesions from 36 lung cancer patients was used for evaluation. Results Due to small sample size issue, the result was exploratory in nature. By analyzing RECIST target lesion data, the LeHeC approach detected a high prevalence (n = 21; 58%) of lesion heterogeneity. Subgroup classification revealed several informative distinct subsets in a descending order of lesion heterogeneity: mix of progression and regression (n = 7), mix of progression and stability (n = 9), mix of regression and stability (n = 5), and non-heterogeneity (n = 15). Evaluation for association of lesion heterogeneity and RECIST best response classification showed lesion heterogeneity commonly occurred in each response group (stable disease: 16/27; 59%; partial response: 3/5; 60%; progression disease: 2/4; 50%). Survival analysis showed a differential trend of overall survival between heterogeneity and non-heterogeneity in RECIST response groups. Conclusion This is the first study to evaluate lesion heterogeneity, an underappreciated metric, for RECIST application in oncology clinical trials. Results indicated lesion heterogeneity is not an uncommon event. The LeHeC approach could enhance RECIST response classification by utilizing granular lesion level discovery of heterogeneity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Persons with disabilities can have physical, mental, intellectual, or sensory impairments which can hinder their social participation. Despite Sustainable Development Goals call for "universal access ...to sexual and reproductive health (SRH)", women with disabilities (WwDs) continue to experience barriers to access SRH services in Nepal. This study evaluated factors affecting the utilization of SRH services among WwDs in Ilam district, Nepal.
A mixed-method study with 384 WwDs of reproductive age was conducted in Ilam district, eastern Nepal. Quantitative data were collected using a structured questionnaire. Relationships between utilization of SRH services and associated factors were explored using multivariate logistic regression analysis. Qualitative data were collected from focus groups with female community health volunteers and interviews with WwDs, health workers and local political leaders. They were audio-recorded, translated and transcribed into English and were thematically analyzed.
Among 384 respondents (31% physical; 7% vision,16% hearing, 7% voice&speech,12% mental/psychosocial, 9% intellectual, 18% multiple disabilities), only 15% of them had ever utilized any SRH services. No requirement (57%) and unaware of SRH services (24%) were the major reasons for not utilizing SRH services. A majority (81%) of them reported that the nearest health facility was not disability-inclusive (73%), specifically referring to the inaccessible road (48%). Multivariate analysis showed that being married (AOR = 121.7, 95% CI: 12.206-1214.338), having perceived need for SRH services (AOR = 5.5; 95% CI: 1.419-21.357) and perceived susceptibility to SRH related disease/condition (AOR = 6.0; 95% CI:1.978-18.370) were positively associated with the utilization of SRH services. Qualitative findings revealed that illiteracy, poor socioeconomic status, and lack of information hindered the utilization of SRH services. WwDs faced socioeconomic (lack of empowerment, lack of family support), structural (distant health facility, inaccessible-infrastructure), and attitudinal (stigmatization, bad behaviour of health care providers, perception that SRH is needed only for married) barriers to access SRH services.
Utilization of SRH services among WwDs was very low in Ilam district, Nepal. The findings of this study warrant a need to promote awareness-raising programs to WwDs and their family members, sensitization programs to health service providers, and ensure the provision of disability-inclusive SRH services in all health facilities.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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