Background
Immune-related adverse events (irAEs) comprise a distinct spectrum of auto-inflammatory manifestations triggered due to immune checkpoint inhibitors (ICI). Current data on the association ...of irAEs with outcomes in NSCLC treated with nivolumab are limited.
Methods and objectives
We pooled data from 531 metastatic NSCLC patients from five centers treated with nivolumab after failing platinum-based chemotherapy. The primary objective was to investigate the relationship between irAEs with clinical benefit to nivolumab as well as to elucidate patterns of irAE-related ICI discontinuations and their impact on survival.
Results
33.0% (173/531) of patients treated with nivolumab were noted to have an irAE. Patients with irAEs had a significantly longer median PFS 6.1 vs. 3.1 months, HR 0.68 95% CI (0.55–0.85);
p
= 0.001 and OS 14.9 vs. 7.4 months, HR 0.66 95% CI (0.52–0.82);
p
< 0.001) compared to those without irAEs. In multivariate analysis, the presence of irAEs showed a significantly better PFS HR 0.69, 95% CI (0.55–0.87);
p
= 0.002 and a trend for better OS HR 0.62, 95% CI (0.55–1.03);
p
= 0.057. Patients with permanent ICI discontinuation secondary to index irAE had a significantly shorter median PFS 2.3 vs. 6.6 months, HR 1.74 95% CI (1.06–2.80);
p
= 0.02 and median OS 3.6 vs. 17.6 months; HR 2.61 95% CI (1.61–4.21);
p
< 0.001 compared to those that did not have permanent ICI discontinuation.
Conclusions
Our pooled exploratory analysis demonstrates improved clinical benefit to nivolumab in NSCLC patients experiencing irAEs. We also observed negative impact of irAE-related treatment discontinuation on survival in this group of patients.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., ...2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca
-signals and non-selective cation currents, the other weaker Ca
-signals and Na
-selective currents. These properties were mirrored by the Ca
-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P
, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.
Introduction
Immune checkpoint inhibitors (ICI) are associated with unique immune-related adverse events (irAEs). Immune-related thrombocytopenia (irTCP) is an understudied and poorly understood ...toxicity; little data are available regarding either risk of irTCP or the effect of irTCP on clinical outcomes of patients treated with ICI.
Methods
We conducted a retrospective review of sequential cancer patients treated with ICI between 2011 and 2017 at our institution. All patients who received ICI alone or in combination with other systemic therapy in any line of treatment were included; those with thrombocytopenia ≥ grade 3 at baseline were excluded. We calculated the incidence of ≥ grade 3 irTCP and overall survival (OS). Patient factors associated with irTCP were assessed.
Results
We identified 1,038 patients that met eligibility criteria. Overall, 89 (8.6%) patients developed grade ≥ 3 thrombocytopenia; eighteen were attributed to ICI (1.73% overall). Patients who developed grade ≥ 3 irTCP had worse overall survival compared to those whose thrombocytopenia was unrelated to ICI (4.17 vs. 10.8 month; HR. 1.94, 95% CI 1.13, 3.33; log-rank
p
= 0.0164). Patients with grade ≥ 3 irTCP also had worse survival compared to those without thrombocytopenia (4.17 vs. 13.31 months; HR 2.22, 95% CI 1.36, 3.62; log-rank
p
= 0.001). The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy (
p
= 0.059) and was not associated with cancer type, smoking status, age, gender, race, or line of therapy.
Conclusions
Unlike other irAEs, we found that irTCP was associated with worse overall survival. The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Multiple studies have found the neutrophil to lymphocyte ratio (NLR) to be associated with adverse breast cancer (BC) prognosis and survival. Very limited data exist on the role of NLR and risk of ...BC. The BREOGAN study is a population-based case-control study conducted in Galicia, Spain. We examined the WBC- and NLR-BC relationships. The risk of BC increased with increasing levels of neutrophils percentage (NE%) (multivariable OR for the highest category (95% CI) = 2.14 (1.39-3.32), P-trend < 0.001) and of the NLR (multivariable OR for the highest category (95% CI) = 1.93 (1.26-2.97), P-trend < 0.001). Lymphocytes absolute (L#) and percentage (L%) were associated with a decreased risk of BC (multivariable OR for the highest category (95% CI) = 0.54 (0.35-0.83), and 0.51 (0.33-0.79), P-trend = 0.001 and < 0.001, respectively). The NLR-BC association was more pronounced among Luminal A BC (multivariable OR for the highest category (95% CI) = 2.00 (1.17-3.45), P-trend < 0.001), HER2-negative BC (multivariable OR for the highest category (95% CI) = 1.87 (1.16-3.02), P-trend < 0.001), and those with high total cholesterol and low H
O
levels.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Liquid chromatography with tandem mass spectrometry is used widely used for the quantitative analysis of phytoconstituents present in medicinal plants to assess the quality of extract used for ...different investigations.
A sensitive, precise, and accurate liquid chromatographic method with tandem mass spectrometric detection was developed for simultaneous quantification of lupeol, betulinic acid, and β-sitosterol in the methanolic extract of Madhuca longifolia bark.
The three compounds were eluted with a stationary phase Gemini C18 column (50 × 2.0 mm, 3 μm id) and the temperature of the column was maintained by a column oven at 40 ± 0.3°C; mobile phase A (water and 0.1% formic acid) and mobile phase B acetonitrile-methanol (50+50, v/v) and 0.1% formic acid were used in a gradient mode and the flow rate was 0.4 mL/min.
With these conditions, the retention time for betulinic acid, lupeol, and β-sitosterol was found to be 1.25, 3.08, and 3.53 minutes, respectively. The total run time was 5.0 min. Detection and quantitation of all three phytoconstituents were carried out by the mass spectrometer, a triple quadrupole equipped with atmospheric pressure chemical ionization, and multiple reaction monitoring using the predominantly positive ion mode and obtained much higher and more stable response nebulizer gas flow at 3.0 L/min. Linear responses were exhibited for all three phytoconstituents with a dynamic linear range of 10-100 μg/mL with the values of the regression coefficient more than 0.995 for betulinic acid, lupeol, and β-sitosterol. The values of percentage RSD for intraday and interday precision were found to be within the accepted limits for analytical methods (<15%). Selectivity, linearity, LOD, LOQ, accuracy, and precision were evaluated for all three phytoconstituents as per International Conference on Harmonization guidelines.
The proposed method is accurate and sensitive and can be used for the routine quantification of betulinic acid, lupeol, and β-sitosterol from the herbal extract and its poly-herbal formulations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Membrane contact sites are regions of close apposition between organelles that facilitate information transfer. Here, we reveal an essential role for Ca2+ derived from the endo-lysosomal system in ...maintaining contact between endosomes and the endoplasmic reticulum (ER). Antagonizing action of the Ca2+-mobilizing messenger NAADP, inhibiting its target endo-lysosomal ion channel, TPC1, and buffering local Ca2+ fluxes all clustered and enlarged late endosomes/lysosomes. We show that TPC1 localizes to ER-endosome contact sites and is required for their formation. Reducing NAADP-dependent contacts delayed EGF receptor de-phosphorylation consistent with close apposition of endocytosed receptors with the ER-localized phosphatase PTP1B. In accord, downstream MAP kinase activation and mobilization of ER Ca2+ stores by EGF were exaggerated upon NAADP blockade. Membrane contact sites between endosomes and the ER thus emerge as Ca2+-dependent hubs for signaling.
Display omitted
•NAADP/TPC1 signaling maintains endo-lysosomal morphology•TPC1 localizes to contacts between late endosomes and the endoplasmic reticulum•NAADP/TPC1 signaling regulates contact site formation•NAADP tempers EGF receptor-mediated signaling
Endosomes form junctions with the ER, but how this contact is regulated remains unclear. Kilpatrick et al. find that Ca2+ release by an endosomal ion channel facilitates inter-organellar coupling to temper signals mediated by an internalized growth factor receptor. Endosome-ER contact sites thus emerge as Ca2+-dependent signaling hubs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Quinolines are a prominent heterocyclic motif and crucial building blocks in creating physiologically active compounds. Due to the fast development of novel medicines with a quinoline nucleus, ...numerous research papers have been published in a short amount of time. Therefore, to comprehend the present state of the quinoline nucleus in medicinal chemistry science, it is necessary to combine new information with older data. So far, several traditional synthesis techniques have been reported in the literature to synthesize this scaffold. Pfitzinger, Gould-Jacob, Friedlander, Skraup, Doebner-von Miller, and Conrad-Limpach are examples of old synthetic methods. However, they need expensive and demanding conditions, such as high temperature, the use of non-biodegradable chemical compounds degrade the ecosystem, create irritation or harm as pollutants, and represent a threat to the environment. However, traditional synthesis processes need a difficult and time-consuming apparatus set-up, resulting in high costs and pollutants. As a result, scientists are presently developing new and innovative techniques to decrease the use of chemicals, solvents, and catalysts, which are detrimental to both humans and the environment. Therefore, we have attempted to shed light in this current review on various reactions to produce quinolines and their derivatives using various green synthetic methods.
Background
Adjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. ...However, known biomarkers like PD-L1 are not consistently indicative of ICB response. Other markers within the tumor immune microenvironment (TIME) may better reflect ICB response and/or resistance mechanisms, but an understanding of how TIMEs differ between stage III and IV NSCLC has not been explored.
Methods
Real-world data from unresectable, stage III-IV, non-squamous, pretreatment NSCLCs (stage III
n
= 106, stage IV
n
= 285) were retrospectively analyzed. PD-L1 immunohistochemistry (IHC) was compared to
CD274
gene expression. Then, differential gene expression levels, pathway enrichment, and immune infiltrate between stages were calculated from whole-transcriptome RNA-seq. Analyses were stratified by
EGFR
status.
Results
PD-L1 IHC and
CD274
expression in tumor cells were highly correlated (
n
= 295,
P
< 2.2e-16,
⍴
= 0.74).
CTLA4
expression was significantly increased in stage III tumors (
P
= 1.32e-04), while no differences were observed for other ICB-related genes. Metabolic pathway activity was significantly enriched in stage IV tumors (
P
= 0.004), whereas several immune-related KEGG pathways were enriched in stage III. Stage IV tumors had significantly increased macrophage infiltration (
P
= 0.0214), and stage III tumors had a significantly higher proportion of CD4 + T cells (
P
= 0.017). CD4 + T cells were also relatively more abundant in
EGFR
-mutant tumors vs. wild-type (
P
= 0.0081).
Conclusion
Directly comparing the TIMEs of stage III and IV NSCLC, these results carry implications for further studies of ICB response in non-resectable stage III NSCLC and guide further research of prognostic biomarkers and therapeutic targets.
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EMUNI, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Bispecific T cell-engaging (BiTE) antibodies recruit polyclonal cytotoxic T cells (CTL) to tumors. One such antibody is carcinoembryonic antigen (CEA) BiTE that mediates T cell/tumor interaction by ...simultaneously binding CD3 expressed by T cells and CEA expressed by tumor cells. A widely operative mechanism for mitigating cytotoxic T cell-mediated killing is the interaction of tumor-expressed PD-L1 with T cell-expressed PD-1, which may be partly reversed by PD-1/PD-L1 blockade. We hypothesized that PD-1/PD-L1 blockade during BiTE-mediated T cell killing would enhance CTL function. Here, we determined the effects of PD-1 and PD-L1 blockade during initial T cell-mediated killing of CEA-expressing human tumor cell lines in vitro, as well as subsequent T cell-mediated killing by T lymphocytes that had participated in tumor cell killing. We observed a rapid upregulation of PD-1 expression and diminished cytolytic function of T cells after they had engaged in CEA BiTE-mediated killing of tumors. T cell cytolytic activity in vitro could be maximized by administration of anti-PD-1 or anti-PD-L1 antibodies alone or in combination if applied prior to a round of T cell killing, but T cell inhibition could not be fully reversed by this blockade once the T cells had killed tumor. In conclusion, our findings demonstrate that dual blockade of PD-1 and PD-L1 maximizes T cell killing of tumor directed by CEA BiTE in vitro, is more effective if applied early, and provides a rationale for clinical use.
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EMUNI, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a widespread and potent calcium-mobilizing messenger that is highly unusual in activating calcium channels located on acidic stores. However, ...the molecular identity of the target protein is unclear. In this study, we show that the previously uncharacterized human two-pore channels (TPC1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpression of TPC1 and attenuated after knockdown of TPC1, and that mutation of a single highly conserved residue within a putative pore region abrogated calcium release by NAADP. Thus, TPC1 is critical for NAADP action and is likely the long sought after target channel for NAADP.
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