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The purpose of the study was to test the within-week variations of the internal and external training intensity outcomes organized by days of the week. An 8-month observational period was conducted during the 2020-2021 season. The training sessions and matches of an elite volleyball team were monitored daily. The data comes from 14 players (two setters, five middle blockers, five outside hitters, and two opposites) of an elite team from the Portuguese 1st League (age: 21.7 ± 4.19 years of age; experience: 6.2 ± 3.8 years; body mass: 85.7 ± 8.69 kg; height: 192.4 ± 6.25 cm; BMI: 23.1 ± 1.40 kg/m 2 ). The CR10 Borg scale was applied daily to measure the training intensity. The rate of perceived exertion (RPE) and the session-RPE were extracted as the internal outcomes. The external intensity was measured using an inertial measurement unit (IMU). The number of jumps, height average of jumps (JHA), minimum jump (MJ), maximal jump (MXJ), range jump (RJ), number of jumps (NJ), and training session density (D) were extracted as external intensity outcomes. The results showed that there was a difference between RPE and S-RPE (F (1.98) = 6.31, p = 0.01, η 2 = 0.36, and F (1.73) = 28.30, p = 0.001, η 2 = 0.72), as well as JHA and NJ (F (2.14) = 4.76, p = 0.02, η 2 = 0.30, and F (1.77) = 4.77, p = 0.02, η 2 = 0.30) within the microcycle. When analyzing the correlations between internal and external intensity, it was observed that there was a negative correlation between the Maximum Jump (4, 3, and 1 days before the Match day) (r 2 = 0.34, r 2 = 0.40, r 2 = 0.41, respectively) and the Range Jump (3 and 1 days before the Match day (r 2 = 0.33, r 2 = 0.38, respectively) with the RPE (4 days before the Match day) and Maximum Jump (5, 4, 3, and 1 days before the Match day (r 2 = 0.35, r 2 = 0.39, r 2 = 0.44, r 2 = 0.34, respectively) and Range Jump (5, 4, 3, and 1 days before the Match day) (r 2 = 0.34, r 2 = 0.35, r 2 = 0.40 and r 2 = 0.36, respectively) with S_RPE (4 days before the Match day). Such findings show that higher internal intensities are correlated with lower external intensities in sessions further away from the game day. Such results could be an important tool for coaches to reflect, plan, monitor, and execute the training unit according to the temporal distance to the competition.

Designing specific therapies for drug-resistant cancers is arguably the ultimate challenge in cancer therapy. While much emphasis has been put on the study of genetic alterations that give rise to drug resistance, much less is known about the non-genetic adaptation mechanisms that operate during the early stages of drug resistance development. Drug-tolerant persister cells have been suggested to be key players in this process. These cells are thought to have undergone non-genetic adaptations that enable survival in the presence of a drug, from which full-blown resistant cells may emerge. Such initial adaptations often involve engagement of stress response programs to maintain cancer cell viability. In this review, we discuss the nature of drug-tolerant cancer phenotypes, as well as the non-genetic adaptations involved. We also discuss how malignant cells employ homeostatic stress response pathways to mitigate the intrinsic costs of such adaptations. Lastly, we discuss which vulnerabilities are introduced by these adaptations and how these might be exploited therapeutically.

The increased usage of high-throughput technologies in cancer research, including genetic and drug screens, generates large sets of candidate targets that need to be functionally validated for their roles in tumor development. Thus, reliable and robust in vivo model systems are needed to perform reverse genetic experiments. Ideally, these models should allow for a conditional silencing of the target and an unambiguous identification of engineered cancer cells. Here, we present a platform consisting of: (i) t(8;21) and t(15;17) driven acute myeloid leukemia (AML) transgenic mice with constitutive expression of green fluorescent protein (GFP) and inducible expression of Cre recombinase, and (ii) REX, a modified pSico lentiviral vector for inducible shRNA expression and red fluorescent protein (RFP) as a selection marker. In this system, leukemic cells from transgenic mice are transduced with REX, flow sorted, and transplanted into syngeneic hosts. Gene interference is induced in established tumors by tamoxifen treatment. Dual-color cell fluorescence guides the in vivo identification of shRNA interfered AML cells, monitoring engraftment and disease progression. We tested the platform by inducing knockdown of Zeb2, a gene upregulated by AML1-ETO and PML-RARα oncogenes in pre-leukemic hematopoietic stem cell compartment, and observed a significant delay in leukemia onset. This proves the power and utility of the platform and confirms Zeb2 contribution to the pathogenesis of AML.