Local and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for Stage III non-small-cell lung cancer. We conducted preclinical studies of docetaxel's cytotoxic and ...radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low-dose radiosensitizing docetaxel CRT.
A preclinical study was conducted in human lung cancer cell lines NCI 520 and A549. Cells were treated with two concentrations of docetaxel for 3 h and then irradiated immediately or after a 24-h delay. A clonogenic survival assay was conducted and analyzed for cytotoxic effects vs. radiosensitizing effects of docetaxel. A pilot clinical study was designed based on preclinical study findings. Twenty-two patients were enrolled with a median follow-up of 4 years. Induction chemotherapy consisted of 75 mg/m(2) of docetaxel and 75 mg/m(2) of cisplatin on Day 1 and 150 mg/m(2) of recombinant human granulocyte colony-stimulating factor on Days 2 through 10. Concurrent CRT was started 3 to 6 weeks later with twice-weekly docetaxel at 10 to 12 mg/m(2) and daily delayed radiation in 1.8-Gy fractions to 64.5 Gy for gross disease.
The preclinical study showed potent cytotoxic effects of docetaxel and subadditive radiosensitizing effects. Delaying radiation resulted in more cancer cell death. The pilot clinical study resulted in a median survival of 32.6 months for the entire cohort, with 3- and 5-year survival rates of 50% and 19%, respectively, and a distant metastasis-free survival rate of 61% for both 3 and 5 years. A pattern-of-failure analysis showed 75% chest failures and 36% all-distant failures. Therapy was well tolerated with Grade 3 esophagitis observed in 23% of patients.
One-cycle full-dose docetaxel/cisplatin induction chemotherapy with recombinant human granulocyte colony-stimulating factor followed by pulsed low-dose docetaxel CRT is promising with regard to its antitumor activity, low rates of distant failure, and low toxicity, suggesting that this regimen deserves further investigation.
Mean-shift is an iterative procedure often used as a nonparametric clustering algorithm that defines clusters based on the modal regions of a density function. The algorithm is conceptually appealing ...and makes assumptions neither about the shape of the clusters nor about their number. However, with a complexity of
(
) per iteration, it does not scale well to large data sets. We propose a novel algorithm which performs density-based clustering much quicker than mean-shift, yet delivering virtually identical results. This algorithm combines subsampling and a stochastic approximation procedure to achieve a potential complexity of
(
) at each step. Its convergence is established. Its performances are evaluated using simulations and applications to image segmentation, where the algorithm was tens or hundreds of times faster than mean-shift, yet causing negligible amounts of clustering errors. The algorithm can be combined with existing approaches to further accelerate clustering.
A flow cytometric, anti-CD71-based method was used to measure peripheral blood reticulocyte and micronucleated reticulocyte frequencies in response to
137Cs total body irradiation (TBI). In three ...independent experiments, groups of five female C57BL/6N mice were irradiated at graded doses up to 3
Gy, and peripheral blood specimens were collected at 43
h post-irradiation. Whereas the frequency of reticulocytes declined over the range of doses studied, micronucleated reticulocyte incidence was observed to increase in a dose-dependent manner up to 1
Gy. At doses greater than approximately 1
Gy, micronucleated reticulocyte frequencies declined with increasing exposure. These responses were highly reproducible, with significant effects on reticulocyte and micronucleated reticulocyte frequencies observed for the lowest dose studied (0.125
Gy). A time-course experiment was performed to test whether radiation-induced cell cycle delay may explain saturation of the micronucleated reticulocyte endpoint at doses >1
Gy. For this experiment, groups of four female C57BL/6N mice were exposed to 1, 1.5, or 2
Gy TBI, and blood collection occurred at 12
h intervals from 43 to 115
h post-exposure. Reduced reticulocyte frequencies were observed for each dose studied, and the recovery of reticulocytes was increasingly delayed with higher radiation doses. Maximal micronucleated reticulocyte frequencies were observed at 43 or 55
h, with progressively lower values at later time points. At no time did micronucleated reticulocyte frequencies induced by 1.5 or 2
Gy significantly exceed that observed for 1
Gy at 43
h. These time-course data suggest that radiation-induced cell cycle delay cannot account for the micronucleated reticulocyte downturn phenomenon observed at doses greater than 1
Gy. An alternate hypothesis is discussed whereby apoptotic elimination of severely damaged bone marrow erythroid precursors plays a dominant role in saturating the radiation-induced micronucleated reticulocyte response observed for C57BL/6N mice.
We investigate multitype subcritical Markov branching processes with immigration driven by Poisson random measures. Limiting distributions are established for various rates of the Poisson measures ...when they are asymptotically equivalent to exponential or regularly varying functions. Results analogous to a strong LLN are proved, and limiting normal distributions are obtained when the local intensity of the Poisson measure increases with time. When it decreases, conditional limiting distributions are established. When the intensity converges to a constant, a stationary limiting distribution is obtained. The asymptotic behavior of the first and second moments of the processes is also investigated.
Several vaccine candidates to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19) have entered or will soon enter ...large-scale, phase 3, placebo-controlled randomized clinical trials. To facilitate harmonized evaluation and comparison of the efficacy of these vaccines, a general set of clinical endpoints is proposed, along with considerations to guide the selection of the primary endpoints on the basis of clinical and statistical reasoning. The plausibility that vaccine protection against symptomatic COVID-19 could be accompanied by a shift toward more SARS-CoV-2 infections that are asymptomatic is highlighted, as well as the potential implications of such a shift.
Age-dependent branching processes are increasingly used in analyses of biological data. Despite being central to most statistical procedures, the identifiability of these models has not been studied. ...In this paper we partition a family of age-dependent branching processes into equivalence classes over which the distribution of the population size remains identical. This result can be used to study identifiability of the offspring and lifespan distributions for parametric families of branching processes. For example, we identify classes of Markov processes that are not identifiable. We show that age-dependent processes with (nonexponential) gamma-distributed lifespans are identifiable and that Smith-Martin processes are not always identifiable.
Age-dependent branching processes are increasingly used in analyses of biological data. Despite being central to most statistical procedures, the identifiability of these models has not been studied. ...In this paper we partition a family of age-dependent branching processes into equivalence classes over which the distribution of the population size remains identical. This result can be used to study identifiability of the offspring and lifespan distributions for parametric families of branching processes. For example, we identify classes of Markov processes that are not identifiable. We show that age-dependent processes with (nonexponential) gamma-distributed lifespans are identifiable and that Smith-Martin processes are not always identifiable.
We consider multitype Markov branching processes with immigration occurring at time points generated by Poisson random measures. These models find applications to study evolution of multitype cell ...populations in which new cells join the population according to a time-varying immigration mechanism. The focus of this paper is the supercritical case. We investigate the limiting behavior of the process for different rates of the Poisson random measures. In particular, we prove a result analogous to a strong LLN and establish limiting normal distributions.
The adverse effects of chemotherapy on normal cells of the body create substantial clinical problems for many cancer patients. However, relatively little is known about the effects, other than ...promotion of cell death, of such agents on the function of normal precursor cells critical in tissue homeostasis and repair. We have combined mathematical and experimental analyses to identify the effects of sublethal doses of chemotherapy on glial precursor cells of the central nervous system. We modeled the temporal development of a population of precursor and terminally differentiated cells exposed to sublethal doses of carmustine (BCNU), a classic alkylating chemotherapeutic agent used in treatment of gliomas and non-Hodgkin's lymphomas, as a multitype age-dependent branching process. We fitted our model to data from in vitro clonal experiments using the method of pseudo-likelihood. This approach identifies several novel drug effects, including modification of the cell cycle length, the time between division and differentiation, and alteration in the probability of undergoing self-renewal division in precursor cells. These changes of precursor cell function in the chemotherapy-exposed brain may have profound clinic implications.
We applied our computational approach to analyze the effects of BCNU on clonal cultures of oligodendrocyte progenitor cells-one of the best-characterized neural progenitor cells in the mammalian brain. Our analysis reveals that transient exposures to BCNU increased the cell cycle length of progenitor cells and decreased their time to differentiation, while also decreasing the likelihood that they will undergo self-renewing divisions. By investigating the behavior of our mathematical model, we demonstrate that precursor cell populations should recover spontaneously from transient modifications of the timing of division and of differentiation, but such recovery will not happen after alteration of cell fate. These studies identify means by which precursor cell function can be critically compromised by transient exposure to chemotherapy with long-term consequences on the progenitor cell pool even in the absence of drug-induced apoptosis. These analyses also provide novel tools that apply broadly to identify effects of chemotherapeutic agents and other physiological stressors.
The engineered outer domain germline targeting version 8 (eOD-GT8) 60-mer nanoparticle was designed to prime VRC01-class HIV-specific B cells that would need to be matured, through additional ...heterologous immunizations, into B cells that are able to produce broadly neutralizing antibodies. CD4 T cell help will be critical for the development of such high-affinity neutralizing antibody responses. Thus, we assessed the induction and epitope specificities of the vaccine-specific T cells from the IAVI G001 phase 1 clinical trial that tested immunization with eOD-GT8 60-mer adjuvanted with AS01
. Robust polyfunctional CD4 T cells specific for eOD-GT8 and the lumazine synthase (LumSyn) component of eOD-GT8 60-mer were induced after two vaccinations with either the 20- or 100-microgram dose. Antigen-specific CD4 T helper responses to eOD-GT8 and LumSyn were observed in 84 and 93% of vaccine recipients, respectively. CD4 helper T cell epitope "hotspots" preferentially targeted across participants were identified within both the eOD-GT8 and LumSyn proteins. CD4 T cell responses specific to one of these three LumSyn epitope hotspots were observed in 85% of vaccine recipients. Last, we found that induction of vaccine-specific peripheral CD4 T cells correlated with expansion of eOD-GT8-specific memory B cells. Our findings demonstrate strong human CD4 T cell responses to an HIV vaccine candidate priming immunogen and identify immunodominant CD4 T cell epitopes that might improve human immune responses either to heterologous boost immunogens after this prime vaccination or to other human vaccine immunogens.
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