Chemotherapy‐induced myelosuppression is an acute, dose‐limiting toxicity of chemotherapy regimens used in the treatment of extensive‐stage small cell lung cancer (ES‐SCLC). Trilaciclib protects ...haematopoietic stem and progenitor cells from chemotherapy‐induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low‐frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all‐cause hospitalisations, all‐cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after Week 5. MAHE and its individual components were assessed in three randomised, double‐blind, placebo‐controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan‐containing chemotherapy regimen for ES‐SCLC and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared to placebo. In the pooled analysis, the cumulative incidences of all‐cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after Week 5 were significantly reduced with trilaciclib vs placebo; however, no significant difference was observed in rates of all‐cause hospitalisations. Additionally, compared to placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES‐SCLC.
The salinity stress tolerance in plants has been studied enormously, reflecting its agronomic relevance. Despite the extensive research, limited success has been achieved in relation to the plant ...tolerance mechanism. The beneficial interaction between
Piriformospora indica
and rice could essentially improve the performance of the plant during salt stress. In this study, the transcriptomic data between
P. indica
treated and untreated rice roots were compared under control and salt stress conditions. Overall, 661 salt-responsive differentially expressed genes (DEGs) were detected with 161 up- and 500 down-regulated genes in all comparison groups. Gene ontology analyses indicated the DEGs were mainly enriched in “auxin-activated signaling pathway”, “water channel activity”, “integral component of plasma membrane”, “stress responses”, and “metabolic processes”. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the DEGs were primarily related to “Zeatin biosynthesis”, “Fatty acid elongation”, “Carotenoid biosynthesis”, and “Biosynthesis of secondary metabolites”. Particularly, genes related to cell wall modifying enzymes (e.g. invertase/pectin methylesterase inhibitor protein and arabinogalactans), phytohormones (e.g. Auxin-responsive Aux/IAA gene family, ent-kaurene synthase, and 12-oxophytodienoate reductase) and receptor-like kinases (e.g. AGC kinase and receptor protein kinase) were induced in
P. indica
colonized rice under salt stress condition. The differential expression of these genes implies that the coordination between hormonal crosstalk, signaling, and cell wall dynamics contributes to the higher growth and tolerance in
P. indica
-inoculated rice. Our results offer a valuable resource for future functional studies on salt-responsive genes that should improve the resilience and adaptation of rice against salt stress.
Novel multifunctional Ba
5
Zn
4
Y
8
O
21
:Tb
3+
nanorods, fabricated via solution combustion route, have been found to go in the tetragonal system with the I4/m (87) crystallographic space group. The ...diffuse reflectance (DR) studies unveiled a band-gap of 3.77 eV for Ba
5
Zn
4
Y
7.84
Tb
0.16
O
21
(most emitting composition). The ultra-violet (UV) excitation at a wavelength of 290 nm for all Ba
5
Zn
4
Y
8
O
21
:Tb
3+
samples produced the characteristics emission peaks corresponding to
5
D
4
→
7
F
6,5,4,3
transitions in Tb
3+
(used to obtain Judd–Ofelt parameters). The critical distance of energy transfer between neighboring Tb
3+
ions was found to be 18.62 Å, and helped to shortlist the right mechanism responsible concentration quenching phenomena (dipole–quadrupole). The in-depth analysis of photoluminescence (PL) decay curves and emission spectra of Ba
5
Zn
4
Y
8
O
21
:Tb
3+
nanorods delivered the value of radiative lifetime (1.1934 ms) and total radiative rates from
5
D
4
state in Tb
3+
. The radiative probabilities of electric-dipole transitions (extracted from total radiative rates i.e. magnetic-dipole + electric-dipole) were used to calculate the Judd–Ofelt intensity parameters (Ω
2
= 3.98 × 10
−20
, Ω
4
= 1.76 × 10
−20
and Ω
6
= 0.28 × 10
−20
cm
2
). The quantum efficiency of
5
D
4
state in Ba
5
Zn
4
Y
7.84
Tb
0.16
O
21
phosphor was calculated to be 79% with pure green emission, signifying their potential use in display and lighting devices. As a final point, the high magnitude of emission cross-section of
5
D
4
→
7
F
5
(14.84 × 10
−20
cm
2
) transition also claims their promising candidature as a good laser crystal.
Background
Supportive care interventions used to manage chemotherapy‐induced myelosuppression (CIM), including granulocyte colony‐stimulating factors (G‐CSFs), erythropoiesis‐stimulating agents ...(ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib.
Methods
Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive‐stage small cell lung cancer (ES‐SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1–4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated.
Results
The use of G‐CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p < 0.0001; 3.3% vs. 11.8%, p = 0.0254; and 14.6% vs. 26.1%, p = 0.0252, respectively). Compared with placebo, trilaciclib significantly reduced DSN and SN, irrespective of G‐CSF administration. RBC transfusions and ESAs were most often administered in patients with grade 3/4 anemia; however, patients typically received RBC transfusions over ESA administration.
Conclusions
By improving CIM and reducing the need for associated supportive care, trilaciclib has the potential to reduce the burden of myelosuppression on patients receiving myelosuppressive chemotherapy for the treatment of ES‐SCLC.
Trial registration
ClinicalTrials.gov (NCT02499770; NCT03041311; NCT02514447).
Compared with placebo, administering trilaciclib prior to chemotherapy reduces chemotherapy‐induced neutropenia and anemia, with a reduction in the use of hematopoietic growth factors and red blood cell transfusions. By improving key myelosuppressive endpoints and reducing the need for associated supportive care, trilaciclib has the potential to reduce both the societal and economic burden of chemotherapy‐induced myelosuppression on patients with extensive‐stage small cell lung cancer.
Combination treatment with chemotherapy and immune checkpoint inhibitors (ICIs) has demonstrated meaningful clinical benefit to patients. However, chemotherapy-induced damage to the immune system can ...potentially diminish the efficacy of chemotherapy/ICI combinations. Trilaciclib, a highly potent, selective and reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in development to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy, has demonstrated proof of concept in recent clinical trials. Furthermore, CDK4/6 inhibition has been shown to augment T-cell activation and antitumor immunity in preclinical settings. Therefore, addition of trilaciclib has the potential to further enhance the efficacy of chemotherapy and ICI combinations.
In murine syngeneic tumor models, a schedule of 3 weekly doses of trilaciclib was combined with chemotherapy/ICI regimens to assess the effect of transient CDK4/6 inhibition on antitumor response and intratumor T-cell proliferation and function. Peripheral T-cell status was also analyzed in patients with small cell lung cancer (SCLC) treated with chemotherapy with or without trilaciclib to gain insights into the effect of transient exposure of trilaciclib on T-cell activation.
Preclinically, the addition of trilaciclib to chemotherapy/ICI regimens enhanced antitumor response and overall survival compared with chemotherapy and ICI combinations alone. This effect is associated with the modulation of the proliferation and composition of T-cell subsets in the tumor microenvironment and increased effector function. Transient exposure of trilaciclib in patients with SCLC during chemotherapy treatment both preserved and increased peripheral lymphocyte counts and enhanced T-cell activation, suggesting that trilaciclib not only preserved but also enhanced immune system function.
Transient CDK4/6 inhibition by trilaciclib was sufficient to enhance and prolong the duration of the antitumor response by chemotherapy/ICI combinations, suggesting a role for the transient cell cycle arrest of tumor immune infiltrates in remodeling the tumor microenvironment. These results provide a rationale for combining trilaciclib with chemotherapy/ICI regimens to improve antitumor efficacy in patients with cancer.
Purpose
Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from ...chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC).
Methods
A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection.
Results
Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m
2
dose would induce a 40–50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m
2
administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m
2
but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m
2
doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m
2
was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03.
Conclusion
Integrated PK/PD, safety, and efficacy data support 240 mg/m
2
as the RP2D for trilaciclib.
ClinicalTrials.gov Identifiers
NCT02243150; NCT02499770; NCT02514447.
To determine whether the instantaneous wave-free ratio (iFR) can detect improvement in stenosis significance after percutaneous coronary intervention (PCI) and compare this with fractional flow ...reserve (FFR) and whole cycle Pd/Pa.
A prospective observational study was undertaken in elective patients scheduled for PCI with FFR ≤ 0.80. Intracoronary pressures were measured at rest and during adenosine-mediated vasodilatation, before and after PCI. iFR, Pd/Pa and FFR values were calculated using the validated fully automated algorithms.
Coronary catheter laboratories in two UK centres and one in the USA.
120 coronary stenoses in 112 patients were assessed. The mean age was 63 ± 10 years, while 84% were male; 39% smokers; 33% with diabetes. Mean diameter stenosis was 68 ± 16% by quantitative coronary angiography.
Pre-PCI, mean FFR was 0.66 ± 0.14, mean iFR was 0.75 ± 0.21 and mean Pd/Pa 0.83 ± 0.16. PCI increased all indices significantly (FFR 0.89 ± 0.07, p<0.001; iFR 0.94 ± 0.05, p<0.001; Pd/Pa 0.96 ± 0.04, p<0.001). The change in iFR after intervention (0.20 ± 0.21) was similar to ΔFFR 0.22 ± 0.15 (p=0.25). ΔFFR and ΔiFR were significantly larger than resting ΔPd/Pa (0.13 ± 0.16, both p<0.001). Similar incremental changes occurred in patients with a higher prevalence of risk factors for microcirculatory disease such as diabetes and hypertension.
iFR and FFR detect the changes in coronary haemodynamics elicited by PCI. FFR and iFR have a significantly larger dynamic range than resting Pd/Pa. iFR might be used to objectively document improvement in coronary haemodynamics following PCI in a similar manner to FFR.
Abstract Ultrasonography remains the screening modality of choice for abdominal aortic aneurysms despite many advances in imaging modalities. Several randomized trials were performed that ...demonstrated the effectiveness of ultrasound-based screening to reduce aneurysm-related mortality. Ultrasound is both cost effective and low risk. Controversies do persist in selecting the appropriate populations for screening, and several national societies have set recommendations.
The pathogenesis of gastrointestinal (GI) symptoms in patients with type 2 diabetes mellitus (T2DM) is yet to be delineated clearly. Serotonin, a monoamine neurotransmitter, resides primarily in the ...gut and plays a vital role in GI system. However, no study has been documented the role of serotonin and serotonin transporter gene (SLC6A4) polymorphism in the development of GI symptoms in T2DM patients.
Three hundred diabetes patients attending diabetes clinic at Postgraduate Institute of Medical Education and Research, Chandigarh, and matched healthy controls were enrolled for this study. Plasma from collected blood sample was used for serotonin measurement by enzyme-linked immunosorbent assay method and buffy coat was used for isolation of DNA by phenol chloroform method. Serotonin transporter gene polymorphism was analyzed by polymerase chain reaction method.
The frequency of short allele (S) and SS genotype was significantly higher in patients with T2DM than controls and was associated with increased risk of T2DM. The frequency of LS genotype showed an association with protection from the disease. Regarding GI symptoms, 78.2% of patients with constipation showed LL and LS genotypes, and 97.7% of patients with diarrhea had SS genotype. The patients without GI symptoms did not show any association of gut motility with genotype. Furthermore, serotonin was significantly higher in diabetic patients who belonged to SS genotype compared to LS or LL genotype and who presented with diarrhea.
SS genotypes are prone to develop diarrhea because of faster gut motility resulting from higher serotonin levels as compared to LS and LL genotype in T2DM patients.
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