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Whole-body vibration (WBV) is a feasible and potentially beneficial exercise strategy for managing neuromuscular impairments like decreased strength or flexibility, mobility limitations and bone health in pediatric cancer survivors. However, as starting rehabilitation as early as possible is recommended to preserve physical function, this study investigated the feasibility of WBV for patients receiving cancer treatment for first cancer diagnosis. Eleven patients (various types of cancer, ages 7–17) participated in the supervised WBV intervention concomitant to acute cancer treatment, which involved chemotherapy. Training was implemented as part of a general exercise program and offered 3 days per week during hospitalization (warm-up, four progressive training exercises comprising 60–120 s, 21–27 Hz, 2 mm peak-to-peak-displacement). Feasibility, which was defined as the absence of WBV-related serious adverse events leading to study dropout, was primarily evaluated. Training documentation was additionally analyzed. As a main result, no serious adverse events leading to study dropout were reported. However, two incidents of bleeding (adverse events) were observed in patients with bleeding tendencies and low platelets (thrombocytes

Nuclear IRF1 is induced following ATG7 and BECN1 knockdown.

dnIRF1 blocks ICI sensitivity in LCC1 cells.

Patient/tumor characteristics of human breast cancer tissue microarrays.

Relationship between IRF1 and ATG7 in human tissue microarrays.

Efficient knockdown of IRF1 using siRNA.

Interferon regulatory factor-1 (IRF1) is a tumor suppressor that regulates cell fate in several cell types. Here, we report an inverse correlation in expression of nuclear IRF1 and the autophagy regulator ATG7 in human breast cancer cells that directly affects their cell fate. In mice harboring mutant Atg7, nuclear IRF1 was increased in mammary tumors, spleen, and kidney. Mechanistic investigations identified ATG7 and the cell death modulator beclin-1 (BECN1) as negative regulators of IRF1. Silencing ATG7 or BECN1 caused estrogen receptor-α to exit the nucleus at the time when IRF1 nuclear localization occurred. Conversely, silencing IRF1 promoted autophagy by increasing BECN1 and blunting IGF1 receptor and mTOR survival signaling. Loss of IRF1 promoted resistance to antiestrogens, whereas combined silencing of ATG7 and IRF1 restored sensitivity to these agents. Using a mathematical model to prompt signaling hypotheses, we developed evidence that ATG7 silencing could resensitize IRF1-attenuated cells to apoptosis through mechanisms that involve other estrogen-regulated genes. Overall, our work shows how inhibiting the autophagy proteins ATG7 and BECN1 can regulate IRF1-dependent and -independent signaling pathways in ways that engender a new therapeutic strategy to attack breast cancer. Cancer Res; 75(6); 1046–55. ©2015 AACR.

Silencing ATG7 and BECN1 induces IRF1 expression independently of ROS.

Model ranges, their range, and description.

Knockdown of IRF1 alters BECN1 and IGF1R/mTOR expression.

Supplementary figure legends

Purpose Colorectal cancer and its treatment are associated with debilitating side effects. Exercise may improve the physical and psychological wellbeing of cancer patients; however, evidence in colorectal cancer patients undergoing adjuvant chemotherapy is limited. This pilot study aimed to explore the effects of supervised aerobic exercise on cardiorespiratory fitness and patient-reported health outcomes in colorectal cancer patients undergoing adjuvant chemotherapy. Methods Patients who had undergone curative resection for colorectal cancer (stages II–III) and were scheduled to receive adjuvant chemotherapy were enrolled into this non-randomized controlled trial. Patients in the intervention group (IG) took part in a 6-month supervised aerobic exercise program, while the control group (CG) received usual care. Cardiorespiratory fitness (measured by peak oxygen consumption) was assessed at baseline and 6 months. Fatigue, quality of life, and physical activity levels were additionally assessed at 3 months. Results In total, 59 patients (33 in IG vs. 26 in CG) were enrolled into this study. Eighteen patients (9 in IG vs. 9 in CG) dropped out of the study prior to the 6-month follow-up. Significant improvements in cardiorespiratory fitness (p = .002) and selected patient-reported health outcomes, such as reduced motivation (p = .015) and mental fatigue (p = .018), were observed in the IG when compared to the CG. Conclusion To our knowledge, this is the first study to investigate the effects of a supervised aerobic exercise program in colorectal cancer patients undergoing adjuvant chemotherapy. The significant and clinically meaningful improvements in CRF warrant further randomized controlled trials to confirm these findings. Trials registration German Clinical Trials Register Identifier: DRKS00005793, 11/03/2014, retrospectively registered.

Background Pediatric cancer leads to reduced participation in exercise and only few patients comply with national physical activity recommendations. Physically inactive behavior hinders motor development and increases physical and psychological adverse effects of therapy and incidence of sequelae. Currently, there is neither nationwide coverage nor uniform level of knowledge regarding exercise promotion. The objective of the guideline is to facilitate qualified exercise interventions through standardized procedures in addition to regular physiotherapy and overall avoid physical inactivity in pediatric cancer patients. Methods This guideline addresses the multidisciplinary treatment team and informs physiotherapists and decision-makers in tertiary care hospitals and health insurance companies. The requirements of the Association of the Scientific Medical Societies in Germany were followed. Contents were based on best practice experience of experts, patient advocates, as well as on scientific evidence. Results The guideline includes 11 recommendations. Recommendations 1-4 declare the relevance of implementing exercise interventions and address general framework conditions. Recommendations 5-11 focus on the design of exercise programs, prevention and safety issues, relative contraindications for specific training loads, and options to overcome barriers to exercise. Conclusion This guideline summarizes existing and established structures and evidence in the context of movement and exercise in pediatric oncology. It takes into consideration the rights, varying needs, and characteristics of children and adolescents as well as national and international experience in this field. In the future, relevant research gaps need to be addressed by high-quality intervention studies to provide the scientific background for a stronger evidence-based guideline.

Background: Breast cancer is associated with many therapy-induced side effects that impact patients’ lives from diagnosis to long-term survivorship. Physical activity has become an important and proven supportive measure in treating side effects like loss of muscle strength, fatigue, chemotherapy-induced peripheral neuropathy, lymphedema, and loss of quality of life. Resistance training (RT) is an established exercise intervention for breast cancer patients, but the correct type, timing, intensity, and duration of exercise remain unclear. It is necessary to investigate different resistance training interventions and their effects on breast cancer patients by covering all stages of treatment, beginning with prehabilitation, through the period of acute therapy, to long-term survivorship. Conclusion: Upon evaluation of randomized controlled trials (RCTs) from the past decade, RT was found to be feasible and safe. Furthermore, there is evidence on the impact of RT on muscle strength, CRF and QoL amongst other factors. Studies implementing mixes of aerobic and strength exercises are rather common, but RCTs of RT-only protocols remain scarce. Different strength training protocols at distinct stages of breast cancer treatment have been conducted, but with the complexity of treatments and the variety of training styles, a large field of study remains. Key Messages: Although the overall data on RT for breast cancer patients has increased, there are many different methodological approaches and testing measures as well as gaps in study documentation. There is still very little of the evidence that would facilitate the compilation of standardized and individualized guidelines.

Background/Aim: Esophagectomy and gastrectomy are procedures with considerable physical burden and intense post-operative care of which the patient’s physical condition seems to be a relevant predictor. The gold standard of the cardiorespiratory fitness is the peak oxygen consumption (VO(2)peak). This pilot study examined the prognostic value of VO(2)peak on post-surgery outcomes in esophageal and gastric cancer patients. Patients and Methods: In this prospective cross-sectional study, patients scheduled for esophagectomy or gastrectomy were examined 24 h before the surgery regarding their VO(2)peak. The post-operative complications according to Clavien-Dindo grade IIIb/IV/V, Intensive-Care-Unit days, and overall hospital stay were documented following surgery. In a subset, body weight changes from surgery until hospital discharge and first aftercare visit were recorded. Results: The functional capacity was significantly reduced in 34/35 of the included patients compared to matched norm-values (p

Purpose: Multiple myeloma (MM) is a severe hemato-oncological disease with high mortality and increasing incidence rate. Since evidence on exercise therapy in MM patients remains limited, this study examines feasibility, adherence, and efficacy based on real-life data from an oncologic care structure.Methods: A data evaluation of MM patients who participated in the oncologic exercise and movement therapy (OTT) at the Cologne University Hospital between 2012 and 2019 was conducted. The patient flow was incrementally reduced to four cohorts, intention-to-treat cohort (ITTC), safety cohort (SC), adherence cohort (AC) and efficacy cohort (EC). Cohorts were evaluated descriptively and by means of correlation analysis as well as group and, time comparisons. Results: 30 patients registered at the OTT between 2012 and 2019 (ITTC). The SC (N = 26) attended exercise therapy on average about one session per week over a period of eight month. One third dropped-out within three months. In the AC (N = 15) BMI at baseline exhibited a strong and very significant negative correlation with exercise adherence. In the EC (N = 8), a significant improvement in physical functioning and a tendency towards significance in fatigue reduction between two measurement points was observed. No adverse events were documented. Conclusions: The present study reveals safety, feasibility and promising findings on adherence and efficacy of exercising MM patients under real-life therapy circumstances. Potential obstacles to exercising such as high BMI might indicate hints for future research. Improvements in physical functioning and tendencies in fatigue reduction should be examined in confirmatory study designs.

Purpose Multiple myeloma (MM) is a severe hemato-oncological disease with high mortality and increasing incidence rate. Since evidence on exercise therapy in MM patients remains limited, this study examines feasibility, adherence, and efficacy based on real-life data from an oncologic care structure. Methods A data evaluation of MM patients who participated in the oncologic exercise and movement therapy (OTT) at the Cologne University Hospital between 2012 and 2019 was conducted. The patient flow was incrementally reduced to four cohorts, intention-to-treat cohort (ITTC), safety cohort (SC), adherence cohort (AC), and efficacy cohort (EC). Cohorts were evaluated descriptively and by means of correlation analysis as well as group and time comparisons. Results Thirty patients registered at the OTT between 2012 and 2019 (ITTC). The SC (N = 26) attended exercise therapy on average about one session per week over a period of 8 months. One-third dropped out within 3 months. In the AC (N = 15), BMI at baseline exhibited a strong and very significant negative correlation with exercise adherence. In the EC (N = 8), a significant improvement in physical functioning and a tendency towards significance in fatigue reduction between two measurement points was observed. No adverse events were documented. Conclusions The present observatory study reveals safety and feasibility while indicating adherence and efficacy of exercising MM patients under real-life therapy circumstances. Found obstacles to exercising as well as improvements in questionnaire scale scores need to be further examined in confirmatory study designs.

Background Rituximab induces a rapid remission in most patients with pemphigus. Objective Our aim was to assess the long-term efficacy of rituximab in this disease. Method We conducted a retrospective study of 59 patients with pemphigus treated with rituximab and observed over a median period of 104 months. Results The rate of complete remission off therapy (CRoff) after the first rituximab cycle was 39%, increasing to 61% with additional rituximab courses. Long-term CRoff was achieved in 27% of patients. The recurrence rate after the first rituximab cycle was 63%, decreasing to approximately 40% with subsequent rituximab cycles. Median time to relapse after the first and subsequent rituximab cycles was 25 months. Renewed rituximab therapy reinduced complete remission in 94% of cases. Baseline anti-desmoglein antibody levels of ≤250 U/mL were significantly associated with the outcome of CRoff. In paired serum samples obtained before the first and six months after the last rituximab therapy, significant reductions of desmoglein-specific autoantibodies were observed. Patients relapsing after a complete remission induced by the first rituximab cycle were more likely to achieve CRoff than patients relapsing after a less favourable outcome and non-responders. There was no significant difference in age, sex, pemphigus subtype, rituximab dosing and disease duration between patients achieving CRoff and those not meeting this end point. Conclusions Lower desmoglein-specific antibody levels at baseline were predictive of CRoff. In patients receiving multiple rituximab cycles, complete remission after the first cycle was associated with a favourable long-term outcome. Repeated rituximab courses were highly effective for relapsed disease and improved the overall outcome.

Purpose To evaluate the residual surface roughness of 5 common diamond-coated interproximal reduction (IPR) systems after consecutive in vitro applications in relation to system, diamond grain size, and instrument thickness. Methods IPR was performed on 80 extracted human incisors using motor-driven strips and discs under predefined conditions. The IPR auxiliaries were applied at 5 consecutive sessions of 20 s on intact interproximal surfaces, and the surface profile (Ra, Rz, Rmax) was analyzed at baseline and after each session with an optical profilometer. Results No overall significant difference in the roughness values was found between systems (P = 0.07 for Ra, P = 0.33 for Rz, and P = 0.48 for Rmax). There was a significant average decrease of Ra, Rz, and Rmax for all systems for every unit increase in time by −0.171 μm (P P ≤ 0.001), and −2.788 μm (P = 0.001), respectively. Ra, Rz, and Rmax values increased significantly, i.e., by 0.194 μm (P = 0.003), 5.890 μm (P = 0.001), and 5.319 μm (P = 0.010) as instrument thickness increased by one unit. No significant reductions in Ra, Rz, and Rmax were observed across grain sizes (−0.008 μm [P > 0.05], −0.244 μm [P > 0.05], and −0.179 μm [P > 0.05], respectively). There was no evidence of interaction between system and time as the P values for Ra, Rz, and Rmax were 0.88, 0.51, and 0.70, respectively. Conclusions All IPR materials presented significant gradual decrease of surface roughness after repeated applications. There were no significant roughness changes among auxiliaries of different grain sizes. Thinner auxiliaries showed significantly more roughness reduction, possibly requiring more frequent replacement than thick auxiliaries in clinical practice.

Physical activity (PA) helps prevention and aftercare of sporadic breast cancer (BC), cardiopulmonary fitness (CPF) being an age-independent predictor of tumor-specific mortality. Therefore, we wanted to identify predictors of CPF (represented by peak oxygen uptake: VO2peak) in BRCA1/2 mutation carriers whose risk of developing BC is high. We used cross-sectional data from 68 BRCA1/2 germline mutation carrying women participating in the randomized, prospective, controlled clinical study LIBRE-1. Assessments included cardiopulmonary exercise testing, medical and lifestyle history plus socioeconomic status. Additionally, the participants completed a psychological questionnaire regarding their attitude, subjective norms, perceived behavior control and intention towards PA. A multivariate logistic regression model was used to identify predictors for participants reaching their age- and sex-adjusted VO2peak reference values. 22 participants (median age: 40 years, interquartile range (IQR) 33–46) were cancer-unaffected and 46 cancer-affected (median age: 44 years, IQR 35–50). The strongest predictor for reaching the reference VO2peak value was attitude towards PA (Odds Ratio 3.0; 95% Confidence Interval 1.3–8.4; p = 0.021). None of the other predictors showed a significant association. A positive attitude towards PA seems to be associated with VO2peak, which should be considered in developing therapeutic and preventive strategies.Trial registrations: NCT02087592; DRKS00005736.

A challenge preventing successful inverse kinematics measurements with heavy nuclei that are not fully stripped is identifying and tagging the beam particles. For this purpose, the HEavy ISotope Tagger (HEIST) has been developed. HEIST utilizes two micro-channel plate timing detectors to measure time of flight, a multi-sampling ion chamber to measure energy loss, and a high purity Ge detector to identify isomer decays and calibrate the isotope identification system. HEIST has successfully identified $^{198}$Pb and other nearby nuclei at energies of about 75 MeV/A. In the experiment discussed, a typical cut containing 89\% of all $^{198}$Pb$^{+80}$ in the beam had a purity of 86\%. We examine the issues of charge state contamination. The observed charge state populations of these ions are presented and are moderately well described by the charge state model GLOBAL., Comment: The following article has been submitted to Review of Scientific Instruments

A High Rigidity Spectrometer (HRS) has been designed for experiments at the Facility for Rare-Isotope Beams (FRIB) at Michigan State University (MSU). The HRS will allow experiments to be performed with the most exotic neutron-rich isotopes at high beam energies ($\gtrsim$100MeV/u). The HRS consists of an analysis beamline called the High-Transmission Beamline (HTBL) and the spectrometer proper called the Spectrometer Section. The maximum magnetic rigidity of the HRS is 8Tm, which corresponds to the rigidities at which rare-isotope beams are optimally produced at FRIB. The resolving power, angular acceptance, and momentum acceptance are set to match the anticipated scientific program. An ion-optical design developed for the HRS is described in detail, along with the specifications of the associated magnet and detector systems., Comment: 24 pages, 26 figures, 6 tables

Introduction Breast cancer survivors are faced with several psychological issues. We report the influence on self-efficacy by a holistic orientated training schedule based on the “Kyusho Jitsu” martial art and explore the effects on self-efficacy, distress, fear, and depression. Methods Breast cancer survivors (N = 51) were randomly assigned to an intervention (n = 30) or control group (n = 21). The intervention group participated in a Kyusho Jitsu intervention twice a week over a period of 6 months, the control group received no intervention. Patients from both groups were measured at baseline, 3 and 6 months on level of self-efficacy (German General-Self-Efficacy Scale, SWE), stress (Perceived Stress Questionnaire, PSQ20), and fear and depression (Hospital Anxiety and Depression Scale, HADS). Results Analysis of the original data showed a significant difference between both groups regarding the subscale “joy” ( P = .018). Several significant results within the intervention group were seen in self-efficacy ( P = .014), fear ( P = .009) and the overall score for fear and depression ( P = .043). Both groups improved significantly within “worries” (intervention P = .006, control P = .019) and the PSQ20 overall score (both P = .005). The control group also significantly improved in the subscale for “demands” ( P = .019). Conclusion To summarize, our pilot study showed that Kyusho Jitsu training is safe and feasible. Though, the intervention alone cannot be considered as being effective enough to help breast cancer survivors regarding relevant psychological issues, but might be an important supplement offer within follow-up care.

This systematic review and meta-analysis of randomized controlled trials determines the efficacy of face-to-face behavior change counseling (BCC) interventions on physical activity (PA) behavior in adult cancer survivors at least pre-and immediately post-intervention compared to usual care. Additionally, this review aims to answer the question which behavior change techniques (BCTs) are most effective. A structured search of the databases Medline, OTseeker, PEDro, the Cochrane Library, and article reference lists was conducted. All trials were critically appraised for methodological quality using the PEDro scale. The BCC interventions were coded using the BCT Taxonomy (v1). Random effect meta-analysis explored between group differences in PA behavior post intervention. Standardized mean differences (SMD) describe effect sizes. Fourteen studies were included, 12 effect sizes within 11 trials were pooled in meta-analysis. The SMD between groups favored the intervention group with a small effect (SMD 0.22; 95% CI 0.11, 0.33; p < 0.0001). The BCTs “graded tasks”, “self-monitoring of behavior”, “action planning” and “habit reversal” were more frequently coded in more efficacious interventions. BCC interventions are effective in increasing PA behavior in cancer survivors. Further research is needed providing details of fidelity assessment and structuring the intervention description by using a BCT taxonomy. Health care professionals should consider our results while awaiting further trial evaluation.Implications for RehabilitationFace-to-face behavior change counseling interventions can significantly increase physical activity behavior in cancer survivors.Although small differences are evident, included trials presented with a broad variety of study components, and characteristics, which limits the interpretation of effective components.The behavior change techniques “Graded tasks”, “Action planning”, “Habit reversal”, and “Credible Source” were used in the trials with a positive effect, but not in the ineffective ones. Face-to-face behavior change counseling interventions can significantly increase physical activity behavior in cancer survivors. Although small differences are evident, included trials presented with a broad variety of study components, and characteristics, which limits the interpretation of effective components. The behavior change techniques “Graded tasks”, “Action planning”, “Habit reversal”, and “Credible Source” were used in the trials with a positive effect, but not in the ineffective ones.

Background Emerging evidence suggests that exercise interventions may improve sexual dysfunction, one of the most common and distressing long-term adverse effects of cancer treatment. Aim The aim of this systematic review is to provide an overview of the effects of exercise on sexual dysfunction in prostate cancer patients. Methods A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The systematic literature search was performed on 13th July 2021 using CINAHL, Cochrane Central Register of Controlled Trials, Embase, Medline and Web of Science. Studies were included if they were randomized controlled trials (RCTs) assessing sexual function in prostate cancer patients conducting an exercise intervention alone or in combination with other supportive interventions. The methodological quality was assessed using the Physiotherapy Education Database Score and Jadad scale. Outcomes were reported as between-group differences. Intragroup differences were also reported if significant. Outcomes Positive intervention effects on sexual function were primarily observed in patients following prostatectomy and undergoing anti-hormone treatment and for pelvic floor muscle exercises as well as aerobic and resistance exercise. RESULTS 22 RCTs (n = 1.752 patients) met the eligibility criteria, conducting either an exercise-only intervention (n = 10), a multimodal (exercise plus other supportive therapy) intervention (n = 4), or pelvic floor muscle exercises (n = 8). 6 RCTs assessed sexual dysfunction as a primary endpoint and 8 RCTs used dedicated assessment methods. 9 of the 22 RCTs found significant between-group differences in favor of the intervention group. Clinical Implications The multifaceted etiology of sexual dysfunction provides a strong rationale to further investigate the effects of exercise on sexual dysfunction in prostate cancer patients and also to consider a multidisciplinary approach. Strengths and Limitations A strength is the comprehensive literature search to identify RCTs involving different exercise interventions and a wide range of sexual function assessments. Further, this is the first systematic review on this topic. The main limitations include the difficulty to compare studies due to the heterogeneity of exercise interventions and low questionnaire completion rates in some studies. CONCLUSION Preliminary data from a small number of studies suggest that certain exercise interventions may improve sexual dysfunction in prostate cancer patients, however further trials involving sexual dyfunction as a primary outcome and more comprehensive assessment tools are needed to confirm the rehabilitative and preventive effects of exercise on sexual dysfunction in prostate cancer patients.

The marine bacterium Vibrio natriegens has recently been demonstrated to be a promising new host for molecular biology and next generation bioprocesses. V. natriegens is a Gram-negative, non-pathogenic slight-halophilic bacterium, with a high nutrient versatility and a reported doubling time of under 10 min. However, V. natriegens is not an established model organism yet, and further research is required to promote its transformation into a microbial workhorse. In this work, the potential of V. natriegens as an amino acid producer was investigated. First, the transcription factor-based biosensor LysG, from Corynebacterium glutamicum, was adapted for expression in V. natriegens to facilitate the detection of positively charged amino acids. A set of different biosensor variants were constructed and characterized, using the expression of a fluorescent protein as sensor output. After random mutagenesis, one of the LysG-based sensors was used to screen for amino acid producer strains. Here, fluorescence-activated cell sorting enabled the selective sorting of highly fluorescent cells, i.e. potential producer cells. Using this approach, individual L-lysine, L-arginine and L-histidine producers could be obtained producing up to 1 mM of the effector amino acid, extracellularly. Genome sequencing of the producer strains provided insight into the amino acid production metabolism of V. natriegens. This work demonstrates the successful expression and application of transcription factor-based biosensors in V. natriegens and provides insight into the underlying physiology, forming a solid basis for further development of this promising microbe., Highlights • Vibrio natriegens is a promising new host for biotechnology. • Transcription factor-based biosensors were expressed in V. natriegens. • Mutagenesis and screening using FACS provided amino acid producing mutants. • Genome sequencing revealed several causal mutations leading to amino acid production. • These results will support further efforts to develop V. natriegens as a production host.

While near-surface geothermal energy applications for the heating and cooling of buildings have been in use for decades, their practical adoption is limited by the energy transport rates through soils. Aquifers provide a means to use convective heat transport to improve heat transfer between the building and the aquifer. However, the solid matrix in the aquifer is carbonaceous in nature, and calcification prevention techniques in the heat exchangers for the building also lead to dissolution of the aquifer matrix. Due to the Arrhenius nature of the reaction, dissolution rates may decrease with increasing temperature. An effective medium model is derived for the energy, calcium species, and fluid transport through a dynamic calcite porous medium which undergoes a reaction between the matrix and fluid. To better discern how these competing phenomena affect thermal transport in the aquifer, a two-dimensional Cartesian system is considered, where the vertical axis is parallel to the borehole axis, and flow is in the horizontal direction. An effective medium model is derived for the energy, calcium species, and fluid transport through a dynamic calcite porous medium which undergoes a reaction between the matrix and fluid. Since the fluid velocity decays algebraically with radial distance from the borehole axis, two flow regimes are considered. In one regime, far from the borehole where flow rates are small, conductive thermal transport acts faster than the species transport, leading to a case where precipitation dominates and regions of the smallest porosity contract to limit energy recovery. In regions with larger porosity, moderate advection of the species is sufficient to prevent significant pore closures over the time scale of exploration. The second regime, closer to the borehole, larger flow rates reduce species concentrations sufficiently to dissolve the solid phase between pores. In this second regime, Taylor dispersion effects in both energy and species transport compete, but thermal conduction acts more slowly than advection, promoting dissolution. The critical limitation in modeling the long-term evolution of the aquifer structure is the in situ dissolution rate.

Oestrogen receptor (ER)-positive breast cancer is responsive to a number of targeted therapies used clinically. Unfortunately, the continuous application of any targeted therapy often results in resistance to the therapy. Our ultimate goal is to use mathematical modelling to optimize alternating therapies that not only decrease proliferation but also stave off resistance. Toward this end, we measured levels of key proteins and proliferation over a 7-day time course in ER+ MCF-7 breast cancer cells. Treatments included endocrine therapy, either oestrogen deprivation, which mimics the effects of an aromatase inhibitor, or fulvestrant, an ER degrader. These data were used to calibrate a mathematical model based on key interactions between ER signalling and the cell cycle. We show that the calibrated model is capable of predicting the combination treatment of fulvestrant and oestrogen deprivation. Further, we show that we can add a new drug, palbociclib, to the model by measuring only two key proteins, cMyc and hyperphosphorylated RB1, and adjusting only parameters associated with the drug. The model is then able to predict the combination treatment of oestrogen deprivation and palbociclib. We illustrate the model's potential to explore protocols that limit proliferation and hold off resistance by not depending on any one therapy. Public Health Service grantUnited States Public Health Service [R01-CA201092, 1P30-CA-51008] This work was partly supported by Public Health Service grant R01-CA201092 to W.T.B. and A.N.S.-H. Technical services were provided by shared resources at Georgetown University Medical Center, including the Tissue Culture Core Shared Resource, that were funded through Public Health Service award 1P30-CA-51008 (Lombardi Comprehensive Cancer Center Support Grant).

Objective: In cancer patients, the impairment in muscle function is a frequently observed phenomenon. However, comprehensive evaluation of the effect of exercise training on muscle function in childhood cancer patients (CCPs) is sparse and therefore investigated in the MUCKI trial. Study Design: In the randomized controlled MUCKI trial, CCPs during intensive cancer treatment and aged 4-18 years were recruited. Eligible patients were enrolled soon after diagnosis as long as they were physically and mentally able to participate in exercise testing and training. Patients of the exercise group (n = 16) participated in average 2.7 ± 1.2 times per week in a combined resistance and endurance training with moderate exercise intensity, for a time period of 8.0 ± 2.1 weeks, while patients of the control group (n = 17) received usual care. Leg strength was evaluated as the primary endpoint. Secondary endpoints were 6-min walk performance, arm strength, body composition, fatigue, and health-related quality of life. Results: Comparisons of pre- and post-intervention results were evaluated by baseline and stratification criteria adjusted analysis and showed positive effects for the exercise group regarding leg strength [F (1, 20) = 5.733; p = 0.027*; η p 2 = 0.223], walking performance [F (1, 25) = 4.270; p = 0.049*; η p 2 = 0.146], fatigue [F (1, 13) = 8.353; p = 0.013*; η p 2 = 0.391], self-esteem [F (1, 6) = 6.823; p = 0.040*; η p 2 = 0.532], and self-reported strength and endurance capacity [F (1, 6) = 6.273; p = 0.046*; η p 2 = 0.511]. No significant differences were found for the other parameters. Conclusion: Within one of the first randomized controlled trials, the present study provides evidence for a positive effect of combined training in CCPs during intensive cancer treatment. Further research is needed to confirm these results and to evaluate their clinical impact. Clinical Trial Registration Number: NCT02612025.

Background: Although psychosomatic medicine is not recognised as a medical specialisation globally, it has proven useful for treating many disorders in Germany. This paper reports on the impact of an educational workshop as a tool for raising awareness about psychosomatic medicine among international psychiatrists. Methods: Psychiatrists from eight different countries were educated on psychosomatic medicine and psychotherapy during a 90-min workshop using a video, a slide presentation and an innovative teaching format called 'speed coaching'. Learning outcomes were assessed by analysing questionnaires completed by the participants before and after the workshop. Results: Half of the participants who initially rejected the notion that psychosomatic medicine should be a specialisation on its own changed their minds in favour for it to be a separate discipline (p = 0.125). Awareness about which diseases and patients psychosomatic doctors deal with was increased. The intent for treatment of patients with eating disorders by a psychosomatic physician quadrupled among the participants (p = 0.004). Conclusions: A brief educational intervention can influence psychiatrists' decisions to opt for approaches by doctors specialized in psychosomatics for certain disorders. Further studies may explore why psychiatrists agree or disagree that psychosomatic medicine should be a separate specialisation on its own. © 2020 The Author(s).

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and clinically relevant side effect of chemotherapy. Approximately 50% of all leukemia, lymphoma, colorectal- and breast cancer patients are affected. CIPN is induced by neurotoxic chemotherapeutic agents and can manifest with sensory and/or motor deficits. It is associated with significant disability and poor recovery. Common symptoms include pain, altered sensation, reduced or absent reflexes, muscle weakness, reduced balance control and insecure gait. These symptoms not only affect activities of daily living, subsequently reducing patients’ quality of life, they have far more become a decisive limiting factor for medical therapy, causing treatment delays, dose reductions, or even discontinuation of therapy, which can affect the outcome and compromise survival. To date, CIPN cannot be prevented and its occurrence presents a diagnostic dilemma since approved and effective treatment options are lacking. Promising results have recently been achieved with exercise. We have revealed that sensorimotor training (SMT) or whole body vibration (WBV) can reduce the symptoms of CIPN and attenuate motor and sensory deficits. We furthermore detected a tendency that it may also have a preventive effect on the onset of CIPN. We are therefore conducting a prospective, multicentre, controlled clinical trial involving 236 oncological patients receiving either oxaliplatin (N = 118) or vinca-alkaloid (N = 118) who are randomized to one of two interventions (SMT or WBV) or a treatment as usual (TAU) group. Primary endpoint is the time to incidence of neurologically confirmed CIPN. Secondary endpoints are pain, maintenance of the functionality of sensory as well as motor nerve fibres as well as the level of physical activity. The baseline assessment is performed prior to the first cycle of chemotherapy. Subsequent follow-up assessments are conducted at 12 weeks, after completion of chemotherapy, and at a 3-month follow-up. Patients who develop CIPN receive an additional assessment at this time point, as it represents the primary endpoint. We hypothesize that SMT and WBV prevent the onset or delay the progression of CIPN, decrease the likelihood of dose reductions or discontinuation of cancer treatment and improve patients’ quality of life. Deutsche Register Klinischer Studien ( DRKS00006088 , registered 07.05.2014).

Physical activity is supposed to decrease mortality of colorectal cancer (CRC) and is suggested to reduce side-effects of the disease and its treatment. However, the knowledge about the influence of exercise interventions on patients suffering from CRC and metastasized CRC (mCRC) is still sparse. One frequently observed side effect in mCRC is chemotherapy-induced peripheral neuropathy (CIPN). This randomized controlled trial investigated the influence of a supervised exercise program on CIPN in mCRC. Thirty patients (stage IV) undergoing outpatient palliative treatment including a median of 23.5 chemotherapy cycles of various regimens were randomly assigned to an intervention or control group (IG, n = 17; CG, n = 13). The IG participated in an eight-week supervised exercise program, including endurance, resistance and balance training (2×/week for 60 min) whereas the CG received written standard recommendations to obtain physical fitness. CIPN was assessed using the FACT/GOG-NTX questionnaire. Moreover, endurance capacity (6MWT), strength (h1RM) and balance (GGT-Reha) were evaluated before (t 0) and after (t 1) the intervention as well as after 4 weeks follow-up (t2). Neuropathic symptoms remained stable in the IG over time, while CIPN significantly worsened in the CG from t 0 to t 1 and t 0 to t 2. In contrast to the CG, the IG significantly improved in strength and balance function. Changes in CIPN correlated with changes in balance. This is the first investigation showing positive effects of a multimodal exercise program on CIPN, balance and strength on mCRC patients in a palliative setting, thereby consequently increasing patients` quality of life. The results support earlier findings stating a positive influence of balance exercise on CIPN.