Fitness Changes in Adolescent Girls Following In-School Combined Aerobic and Resistance Exercise: Interaction With Birthweight.

PURPOSE: To assess the efficacy of a supervised in-school combined resistance and aerobic training program in adolescent girls and investigate whether responses differ according to birthweight. METHODS: Participants (girls aged 13-17 y) were randomized either to an intervention replacing physical education (PE) classes with 2 × 60-minute training sessions per week (n = 58) or to a control group that continued to attend 2 × 60 minutes per week of curriculum PE (n = 41). We measured muscular fitness (handgrip, standing long jump, and sit-ups), cardiorespiratory fitness (20-m shuttle run), skinfolds, and lean body mass preintervention and postintervention and determined effect size (Hedge's g) differences between changes in these measures. We also compared changes within lower (<3000 g) and normal birthweight intervention and PE control subgroups. RESULTS: The intervention group showed greater improvements in all the fitness measures and lean body mass (g = 0.22-0.48) and lower skinfold increases (g = 0.41) than PE controls. Within the intervention group, improvements in all fitness measures were larger in lower birthweight (g = 0.53-0.94) than in normal birthweight girls (g = 0.02-0.39). CONCLUSION: Replacing curriculum PE with supervised training improved muscular and cardiorespiratory fitness and body composition outcomes in adolescent females. Our findings suggest an enhanced adaptive response to training in participants with lower birthweight which warrants further investigation.

Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes.

Tumor-associated macrophages can promote growth of cancers. In neuroblastoma, tumor-associated macrophages have greater frequency in metastatic versus loco-regional tumors, and higher expression of genes associated with macrophages helps to predict poor prognosis in the 60% of high-risk patients who have MYCN-non-amplified disease. The contribution of cytotoxic T-lymphocytes to anti-neuroblastoma immune responses may be limited by low MHC class I expression and low exonic mutation frequency. Therefore, we modelled human neuroblastoma in T-cell deficient mice to examine whether depletion of monocytes/macrophages from the neuroblastoma microenvironment by blockade of CSF-1R can improve the response to chemotherapy. In vitro, CSF-1 was released by neuroblastoma cells, and topotecan increased this release. In vivo, neuroblastomas formed by subcutaneous co-injection of human neuroblastoma cells and human monocytes into immunodeficient NOD/SCID mice had fewer human CD14+ and CD163+ cells and mouse F4/80+ cells after CSF-1R blockade. In subcutaneous or intra-renal models in immunodeficient NSG or NOD/SCID mice, CSF-1R blockade alone did not affect tumor growth or mouse survival. However, when combined with cyclophosphamide plus topotecan, the CSF-1R inhibitor BLZ945, either without or with anti-human and anti-mouse CSF-1 mAbs, inhibited neuroblastoma growth and synergistically improved mouse survival. These findings indicate that depletion of tumor-associated macrophages from neuroblastomas can be associated with increased chemotherapeutic efficacy without requiring a contribution from T-lymphocytes, suggesting the possibility that combination of CSF-1R blockade with chemotherapy might be effective in patients who have limited anti-tumor T-cell responses.

The Relationship between Socioeconomic Status, Family Income, and Measures of Muscular and Cardiorespiratory Fitness in Colombian Schoolchildren.

OBJECTIVE: To determine the associations between socioeconomic status (SES) and physical fitness in a sample of Colombian youth. STUDY DESIGN: Prueba SER is cross-sectional survey of schoolchildren in Bogota, Colombia. Mass, stature, muscular fitness (standing long-jump, handgrip), and cardiorespiratory fitness (20-m shuttle run) were measured in 52?187 schoolchildren 14-16 years of age. Area-level SES was categorized from 1 (very low) to 4 (high) and parent-reported family income was categorized as low, middle, or high. RESULTS: Converting measures into z scores showed stature, muscular, and cardiorespiratory fitness were significantly (z?=?0.3-0.7) below European values. Children in the mid- and high SES groups jumped significantly further than groups with very low SES. Differences were independent of sex but became nonsignificant when adjusted for anthropometric differences. Participants in the mid-SES and high-SES groups had better handgrip scores when adjusted for body dimension. There were, however, no significant between-group differences in cardiorespiratory fitness, which was strongly clustered by school and significantly greater in students from private schools. CONCLUSIONS: Area-level SES is associated with measures of muscular fitness in Colombian schoolchildren. These associations were largely explained by the large differences in body dimensions observed between SES groups. When area-level SES is considered, there was no evidence that family income influenced fitness. The clustering of outcomes reaffirms the potential importance of schools and area-level factors in promoting fitness through opportunities for physical activity. Interventions implemented in schools, can improve academic attainment; a factor likely to be important in promoting the social mobility of children from poorer families.

Sociodemographic factors related to handgrip strength in children and adolescents in a middle income country: The SALUS study.

OBJECTIVE: To determine sociodemographic factors associated with handgrip (HG) strength in a representative sample of children and adolescents from a middle income country. METHODS: We evaluated youth between the ages of 8 and 17 from a representative sample of individuals from the Department of Santander, Colombia. Anthropometric measures, HG strength, and self-reported physical activity were assessed, and parents/guardians completed sociodemographic questionnairres. Multinomial logistic regression models were used to estimate the association between sociodemographic and anthropometric characteristics and tertiles of relative HG strength. We also produced centile data for raw HG strength using quantile regression. RESULTS: 1,691 young people were evaluated. HG strength increased with age, and was higher in males than females in all age groups. Lower HG strength was associated with indicators of higher socioeconomic status, such as living in an urban area, residence in higher social strata neighborhoods, parent/guardian with secondary education or higher, higher household income, and membership in health insurance schemes. In addition, low HG strength was associated with lower physical activity levels and higher waist-to-hip ratio. In a fully adjusted regression model, all factors remained significant except for health insurance, household income, and physical activity level. CONCLUSIONS: While age and gender specific HG strength values were substantially lower than contemporary data from high income countries, we found that within this middle income population indicators of higher socioeconomic status were associated with lower HG strength. This analysis also suggests that in countries undergoing rapid nutrition transition, improvements in socioeconomic conditions may be accompanied by reduction in muscle strength.

Neck circumference as a predictor of metabolic syndrome, insulin resistance and low-grade systemic inflammation in children: the ACFIES study.

BACKGROUND: The current study aims to evaluate the association between neck circumference (NC) and several cardio-metabolic risk factors, to compare it with well-established anthropometric indices, and to determine the cut-off point value of NC for predicting children at increased risk of metabolic syndrome, insulin resistance and low-grade systemic inflammation. METHODS: A total of 669 school children, aged 8-14, were recruited. Demographic, clinical, anthropometric and biochemical data from all patients were collected. Correlations between cardio-metabolic risk factors and NC and other anthropometric variables were evaluated using the Spearman's correlation coefficient. Multiple linear regression analysis was applied to further examine these associations. We then determined by receiver operating characteristic (ROC) analyses the optimal cut-off for NC for identifying children with elevated cardio-metabolic risk. RESULTS: NC was positively associated with fasting plasma glucose and triglycerides (p = 0.001 for all), and systolic and diastolic blood pressure, C-reactive protein, insulin and HOMA-IR (p < 0.001 for all), and negatively with HDL-C (p = 0.001). Whereas, other anthropometric indices were associated with fewer risk factors. CONCLUSIONS: NC could be used as clinically relevant and easy to implement indicator of cardio-metabolic risk in children.

Influence of football match time-motion parameters on recovery time course of muscle damage and jump ability.

We analysed the time course of recovery of creatine kinase (CK) and countermovement jump (CMJ) parameters after a football match, and correlations between changes in these variables and match time-motion parameters (GPS-accelerometry) in 15 U-19 elite male players. Plasma CK and CMJ height (CMJH), average concentric force (CMJCON) and average eccentric force (CMJECC) were assessed 2 h before and 30 min, 24 h and 48 h post-match. There were substantially higher CK levels 30 min, 24 h and 48 h (ES: 0.43, 0.62, 0.40, respectively), post-match. CMJECC (ES: -0.38), CMJH (ES: -0.35) decreased 30 min post, CMJCON (ES: -0.35), CMJECC (ES: -0.35) and CMJH (ES: -1.35) decreased 24 h post, and CMJCON (ES: -0.41) and CMJH (ES: -0.53) decreased 48 h post. We found correlations between distance covered at velocities ≤21 km · h(-1) and changes in CK at 24 h (r = 0.56) and at 48 h (r = 0.54) and correlations between CK and distance covered >14 km · h(-1) (r = 0.50), accelerations (r = 0.48), and decelerations (r = 0.58) at 48 h. Changes in CMJCON 30 min and 24 h post (both r = -0.68) correlated with impacts >7.1·G. Decelerations >2 m · s(-)(2) correlated with changes CMJCON (r = -0.49) at 48 h and CMJECC (r = -0.47) at 30 min. Our results suggest that match GPS-accelerometry parameters may predict muscle damage and changes in components of neuromuscular performance immediately and 24-48 h post-match.

Efficient Preparation of Site-Specific Antibody-Drug Conjugates Using Phosphopantetheinyl Transferases.

Post-translational modification catalyzed by phosphopantetheinyl transferases (PPTases) has previously been used to site-specifically label proteins with structurally diverse molecules. PPTase catalysis results in covalent modification of a serine residue in acyl/peptidyl carrier proteins and their surrogate substrates which are typically fused to the N- or C-terminus. To test the utility of PPTases for preparing antibody-drug conjugates (ADCs), we inserted 11 and 12-mer PPTase substrate sequences at 110 constant region loop positions of trastuzumab. Using Sfp-PPTase, 63 sites could be efficiently labeled with an auristatin toxin, resulting in 95 homogeneous ADCs. ADCs labeled in the CH1 domain displayed in general excellent pharmacokinetic profiles and negligible drug loss. A subset of CH2 domain conjugates underwent rapid clearance in mouse pharmacokinetic studies. Rapid clearance correlated with lower thermal stability of the particular antibodies. Independent of conjugation site, almost all ADCs exhibited subnanomolar in vitro cytotoxicity against HER2-positive cell lines. One selected ADC was shown to induce tumor regression in a xenograft model at a single dose of 3 mg/kg, demonstrating that PPTase-mediated conjugation is suitable for the production of highly efficacious and homogeneous ADCs.

Progressing On-Court Rehabilitation After Injury: The Control-Chaos Continuum Adapted to Basketball.

BACKGROUND: Sport-specific training is an integral component of returning to sport following injury. Frameworks designed to guide sport-specific rehabilitation need to integrate and adapt to the specific context of elite sport. The control-chaos continuum (CCC) is a flexible framework originally designed for on-pitch rehabilitation in elite football (soccer). The concepts underpinning the CCC transfer to other elite sport rehabilitation environments. CLINICAL QUESTION: How can practitioners and clinicians transfer the CCC to elite basketball, to support planning and return to sport? On-court rehabilitation is a critical sport-specific rehabilitation component of return to sport, yet there are no frameworks to guide practitioners when planning and delivering on-court rehabilitation. KEY RESULTS: Based on our experience working in the National Basketball Association, we report how the CCC framework can apply to elite basketball. We focus on the design and delivery of progressive training in the presence of injury in this basketball-specific edition of the CCC. Given the challenges when quantifying "load" in basketball, we encourage practitioners and clinicians to consider the qualitative aspects of performance such as skill, sport-specific movement, contact, and decision making. CLINICAL APPLICATION: The 5-phase framework describes training progression from high control, a return to on-court running, to high chaos, a return to "live" unrestricted basketball. The model can be adapted to both short- and long-term injuries based on injury and progression criteria. Strength and power "diagnostics" can be strategically implemented to enhance decision making throughout the return to sport continuum. J Orthop Sports Phys Ther 2023;53(9):1-12. Epub: 9 August 2023. doi:10.2519/jospt.2023.11981.

Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti-PD-1/PD-L1 Agents.

Immune-checkpoint blockade has revolutionized cancer treatment. However, most patients do not respond to single-agent therapy. Combining checkpoint inhibitors with other immune-stimulating agents increases both efficacy and toxicity due to systemic T-cell activation. Protease-activatable antibody prodrugs, known as Probody therapeutics (Pb-Tx), localize antibody activity by attenuating capacity to bind antigen until protease activation in the tumor microenvironment. Herein, we show that systemic administration of anti-programmed cell death ligand 1 (anti-PD-L1) and anti-programmed cell death protein 1 (anti-PD-1) Pb-Tx to tumor-bearing mice elicited antitumor activity similar to that of traditional PD-1/PD-L1-targeted antibodies. Pb-Tx exhibited reduced systemic activity and an improved nonclinical safety profile, with markedly reduced target occupancy on peripheral T cells and reduced incidence of early-onset autoimmune diabetes in nonobese diabetic mice. Our results confirm that localized PD-1/PD-L1 inhibition by Pb-Tx can elicit robust antitumor immunity and minimize systemic immune-mediated toxicity. These data provide further preclinical rationale to support the ongoing development of the anti-PD-L1 Pb-Tx CX-072, which is currently in clinical trials.

The SIMAC study: A randomized controlled trial to compare the effects of resistance training and aerobic training on the fitness and body composition of Colombian adolescents.

The aim of this study was to evaluate the impact on muscle strength, aerobic fitness and body composition, of replacing the physical education (PE) class of Colombian adolescents with resistance or aerobic training. 120 tanner stage 3 adolescents attending a state school were randomized to resistance training, aerobic training, or a control group who continued to attend a weekly 2- hour PE class for 16 weeks. The resistance training and aerobic training groups participated in twice weekly supervised after-school exercise sessions of < 1 hour instead of their PE class. Sum of skinfolds, lean body mass (bioelectrical impedance analysis), muscular strength (6 repetition maximum (RM)) bench press, lateral pulldown and leg press) and estimated cardiorespiratory fitness (multistage 20 meter shuttle run) were assessed at pre and post intervention. Complete data were available for n = 40 of the resistance training group, n = 40 of the aerobic training group and n = 30 PE (controls). Resistance training attenuated increases in sum of skinfolds compared with controls (d = 0.27, [0.09-0.36]). We found no significant effect on lean body mass. Resistance training produced a positive effect on muscle strength compared with both controls (d = 0.66 [.49-.86]) and aerobic training (d = 0.55[0.28-0.67]). There was a positive effect of resistance training on cardiorespiratory fitness compared with controls (d = 0.04 [-0.10-0.12]) but not compared with aerobic training (d = 0.24 [0.10-0.36]). Replacing a 2-hour PE class with two 1 hour resistance training sessions attenuated gains in subcutaneous adiposity, and enhanced muscle strength and aerobic fitness development in Colombian youth, based on a median attendance of approximately 1 session a week. Further research to assess whether adequate stimuli for the development of muscular fitness exists within current physical education provision is warranted.

Immune enhancement of skin carcinogenesis by CD4+ T cells.

In a transgenic model of multi-stage squamous carcinogenesis induced by human papillomavirus (HPV) oncogenes, infiltrating CD4+ T cells can be detected in both premalignant and malignant lesions. The lymph nodes that drain sites of epidermal neoplasia contain activated CD4+ T cells predominantly reactive toward Staphylococcal bacterial antigens. HPV16 mice deficient in CD4+ T cells were found to have delayed neoplastic progression and a lower incidence of tumors. This delay in carcinogenesis is marked by decreased infiltration of neutrophils, and reduced activity of matrix metalloproteinase-9, an important cofactor for tumor progression in this model. The data reveal an unexpected capability of CD4 T cells, whereby, proinflammatory CD4+ T cells, apparently responding to bacterial infection of dysplastic skin lesions, can inadvertently enhance neoplastic progression to invasive cancer.

Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization.

Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in vivo, probably from premature release of the payload. Second-generation ADCs were then developed, using noncleavable linkers, and the resulting conjugates (ADC-4 and ADC-10) led to in vivo efficacy in an HER-2 expressing (SK-OV-3ip) mouse xenograft model while ADC-11 led to in vivo efficacy in an anti-c-KIT (NCI-H526) mouse xenograft model in a target-dependent manner.

CD4+ T cell-mediated antigen-specific immunotherapy in a mouse model of cervical cancer.

A major agenda for tumor immunology is the generation of specific immune responses leading to the destruction of incipient and frank neoplasia. In this report, we show that a novel HPV16 E7 fusion protein can produce objective therapeutic responses against incipient cervical cancer in genetically engineered mice that express in the cervix the HPV16 early region genes implicated as causative agents in human cervical cancer. Although nonresponsive toward the HPV16 E7 oncoprotein in the CD8+ T-cell compartment by virtue of MHC haplotype, the mice were capable of mounting an induced CD4+ T-cell response against E7, and in addition developed spontaneous anti-E7 antibodies. HPV16/CD4-/- mice showed increased tumor burden indicative of CD4-mediated immune surveillance. Seeking to enhance the CD4 response, we immunized mice bearing incipient cervical cancer with a recombinant protein fusing E7 with a mycobacterial heat shock protein. The incidences of cervical carcinoma and of high-grade dysplasia (CIN 3) were consequently reduced by comparison to control mice. Thus, an HPV16 E7 immunogen holds promise for noninvasive treatment and prevention of human cervical cancer.

Is myopia another clinical manifestation of insulin resistance?

Myopia is a multifactorial visual refraction disease, in which the light rays from distant objects are focused in front of retina, causing blurry vision. Myopic eyes are characterized by an increased corneal curvature and/or ocular axial length. The prevalence of myopia has increased in recent decades, a trend that cannot be attributed exclusively to genetic factors. Low and middle income countries have a higher burden of refractive error, which we propose could be a consequence of a shorter exposure time to a westernized lifestyle, a phenomenon that may also explain the rapid increase in cardiometabolic diseases, such as diabetes, among those populations. We suggest that interactions between genetic, epigenetic and a rapidly changing environment are also involved in myopia onset and progression. Furthermore, we discuss several possible mechanisms by which insulin resistance may promote abnormal ocular growth and myopia to support the hypothesis that insulin resistance and hyperinsulinemia are involved in its pathogenesis, providing a link between trends in myopia and those of cardiometabolic diseases. There is evidence that insulin have direct ocular growth promoting effects as well an indirect effect via the induction of insulin-like growth factors leading to decreases insulin-like growth factor-binding protein, also implicated in ocular growth.