Factorial invariance of the Wechsler Intelligence Scale for Children, Fifth Edition, across the UK, US and Australia & New Zealand.

OBJECTIVES: This study examined the factorial invariance of the factor structure of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) across the UK, US and Australia & New Zealand (A&NZ). The factorial equivalence of cognitive assessments should be demonstrated before assuming cross-culture generalizability and interpretations of score comparisons. METHODS: Data were obtained from the UK, US and A&NZ normative standardizations of the WISC-V. The samples consisted of 415 UK, 2200 US and 528 A&NZ children, aged 6-16. Confirmatory factor analysis was applied separately in each sample to establish the baseline model. Next, tests of factorial invariance were undertaken using the recommended hierarchical approach, firstly across the UK and A&NZ samples and then across the UK and US samples. RESULTS: The five-factor first-order scoring model was found to be excellent fit across all three samples independently. Strict factorial invariance of the WISC-V was demonstrated firstly across the UK and A&NZ and secondly the UK and US nationally representative standardization samples. Comparison of latent means found small but significant differences in female children across the UK and A&NZ samples. CONCLUSIONS: Consistent with previous research, these results demonstrate the generality of the WISC-V factor structure across the UK, US and A&NZ. Furthermore, as the WISC-V factor structure aligns with the Cattell-Horn-Carroll (CHC) model of cognitive abilities, the results add further support to the cross-cultural generalizability of the CHC model. Small but significant differences in latent factor scores found across samples support the development and use of local normative data.

Potential Predictors of Vertical Jump Performance: Lower Extremity Dimensions and Alignment, Relative Body Fat, and Kinetic Variables.

ABSTRACT: Daugherty, HJ, Weiss, LW, Paquette, MR, Powell, DW, and Allison, LE. Potential predictors of vertical jump performance: Lower extremity dimensions and alignment, relative body fat, and kinetic variables. J Strength Cond Res 35(3): 616-625, 2021-The association of structural and kinetic variables with restricted vertical jump (RVJ) displacement without and with added mass was examined in 60 men and women. Added mass (weighted vest) simulated a 5% increase in body fat (BF%). Independent variables included BF%, thigh length, and static Q-angle (Q-angles), and while performing RVJ, different expressions of frontal-plane knee angle (FPKA), dynamic Q-angle (Q-angled), vertical ground reaction force (vGRF), concentric vertical impulse (Iz), concentric rate of force development (CRFD), and vertical power (Pz). Variables having significant (p ≤ 0.05) negative correlations with RVJ displacement included BF% (r = -0.76) and Q-angles (r = -0.55). Those having significant (p ≤ 0.05) positive correlations with RVJ displacement included peak and average concentric Pz (r range = 0.74-0.81), peak and average concentric vGRF (r range = 0.46-0.67), Iz (r range = 0.32-0.54), thigh length (r = 0.31), minimum Q-angled (r = 0.31), and maximum FPKA (r = 0.28). Variables not associated (p > 0.05) with RVJ displacement included minimum and excursion FPKA (r = 0.11 and 0.23), maximum, excursion, and average Q-angled (r = 0.24, 0.11, and 0.22), and CRFD (r range = 0.19-0.24). A simple regression model predicted RVJ displacement (p = 1.00) for the simulated 5% increase in body fat. To maximize jumping performance, (a) high levels of body fat should be avoided, (b) peak and average Pz, vGRF, and Iz should be maximized through training, and (c) having a lower Q-angles is associated with better jumping ability.

Footwear and Sex Differences in Performance and Joint Kinetics During Maximal Vertical Jumping.

Smith, RE, Paquette, MR, Harry, JR, Powell, DW, and Weiss, LW. Footwear and sex differences in performance and joint kinetics during maximal vertical jumping. J Strength Cond Res 34(6): 1634-1642, 2020-This investigation examined the effects of footwear and sex on vertical jump displacement and joint power contributions. Twenty-three young adults with basketball experience performed 3 maximal countermovement vertical jumps in minimal and standard footwear. Ground reaction force and 3D kinematic data were collected during jumping. Footwear by sex analysis of variance for all dependent variables and effect sizes (d) was computed. An interaction effect showed that men produced greater lower-limb-positive work than women in standard footwear. Men jumped higher than women (d = 2.53) and produced greater peak ankle, knee and hip joint moments (d > 0.99), positive joint powers (d > 1.07) and, positive knee and hip joint work (d > 1.04) with no sex differences for negative joint powers and work (p > 0.05). Minimal footwear produced less peak-positive knee power (d = 0.27) and less positive ankle (d = 0.34) and knee (d = 0.21) joint work than standard footwear. Because negative joint power and work were similar between sexes, men may be better able to use the stretch-shortening cycle compared with women. Higher joint mechanical demands may provide a better vertical jumping training stimulus in standard compared with minimal footwear. Future studies should investigate footwear training effects on performance and joint mechanics during jumping.

Immunohistochemical detection of PD-L1 among diverse human neoplasms in a reference laboratory: observations based upon 62,896 cases.

Targeting of the PD1/PD-L1 immune checkpoint pathway has rapidly gained acceptance as a therapeutic strategy for a growing number of malignancies. Testing for expression of PD-L1 in tumor cells and immune cells has been used as a companion or complementary test for drugs targeting the PD1/PD-L1 pathway. We evaluated the results of PD-L1 testing in a large reference lab cohort. Using Food and Drug Administration-approved methods and interpretive instructions for each individual test, 62,896 cases were evaluated for PD-L1 using antibody clone 22C3, 28-8, SP142, or SP263. Case data analyzed included test results and information on tumor location and clinical history. No clinical outcome information was available and no attempt was made to correlate PD-L1 results with any other tests performed. The following numbers of cases were evaluated: 22C3 with tumor proportion score [n = 52585], 22C3 with combined positive score [n = 2631], 28-8 [n = 4191], SP142 [n = 850], and SP263 [n = 70]. In 22C3/tumor proportion score cases, the general results were as follows: negative 33.1% (n = 17,405), (low) expression 33.9% (n = 17,822), and high expression 29.5% (n = 15,486). In cases identified as metastatic, the results were as follows: negative 35.9% (n = 1411), (low) expression 30.8% (n = 1211), and high expression 30.7% (n = 1208). We found broad ranges of expression in tumor types with increasing positivity, as adenocarcinomas were reported as poorly differentiated, whereas squamous cell carcinomas showed more positivity as tumors were described as well-differentiated. The results of many individual tumor types were evaluated and showed, in general, high levels of positive expression. Practical challenges and observations of PD-L1 stain results and interpretation are also discussed.

Immunohistochemistry and alternative FISH testing in breast cancer with HER2 equivocal amplification.

PURPOSE: While HER2 testing is well established in directing appropriate treatment for breast cancer, a small percentage of cases show equivocal results by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Alternative probes may be used in equivocal cases. We present a single community-based institution's experience in further evaluating these cases. PATIENTS AND METHODS: Between 2014 and 2016, 4255 samples were submitted for HER2 amplification testing by alternative probes, TP53, RAI1, and RARA. Of the patients tested by FISH, 505/3908 (12.9%) also had IHC data. RESULTS: Most (73.9%) FISH equivocal cases remained equivocal after IHC testing. However, 50.5% of equivocal cases were classified as HER2 amplified by alternative probes. Most cases were positive by more than one probe: 78% of positive cases by RAI1 and 73.9% by TP53. There was a significant difference between IHC and FISH alternative testing (p < 0.0001) among the equivocal cases by conventional FISH testing, 44% of IHC negative cases became positive while 36% of the positive IHC cases became negative by alternative FISH testing. Available data showed that 41% of patients were treated with palbociclib and were positive by alternative FISH. CONCLUSION: The prevalence of double HER2 equivocal cases and the discrepancy between IHC and alternative FISH testing suggest that FISH alternative testing using both RAI1 and TP53 probes is necessary for conclusive classification. Because almost half of FISH equivocal cases converted to HER2 amplified upon alternative testing, clinical studies to determine the benefit of anti-HER2 therapy in these patients are urgently needed.

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

Potential Utility of a Loaded Treadmill Protocol for Tactical Athletes.

Swearingen, JT, Weiss, LW, Smith, WA, Stephenson, MD, and Schilling, BK. Potential utility of a loaded treadmill protocol for tactical athletes. J Strength Cond Res 32(3): 610-616, 2018-Aerobic capacity is an important variable for tactical athletes, with V[Combining Dot Above]O2max being the most direct way of estimating it in a laboratory setting. A mode-specific protocol involving fixed-weight, torso-borne loads was assessed in the current study. On 4 separate days, 15 men (age 22.1 ± 2.7 years, mass 85.1 ± 10.6 kg, height 179.0 ± 7.7 cm) performed a weighted treadmill walking protocol (2 trials) and a nonweighted treadmill running protocol (2 trials). Both the weighted and nonweighted protocols were reliable, with intraclass correlation coefficient values of 0.79 and 0.87, respectively. V[Combining Dot Above]O2peak values from both protocols were highly correlated (r = 0.90, p < 0.01). However, V[Combining Dot Above]O2peak was higher during the nonweighted protocol (t = 7.547, d = 2.47, p < 0.01). Work rate was calculated for both the last completed stage and stage during which participants reached fatigue. Work rates for both protocols on the last completed stage were similar (t = 1.44, d = 0.83, p = 0.17), although the work rate for the final attempted stage was greater for the weighted-walking protocol (t = 5.85, d = 3.60, p < 0.01). These data suggest a weighted-walking V[Combining Dot Above]O2peak that is highly associated with a running V[Combining Dot Above]O2peak. This test may be applied to those who routinely perform torso-borne load carriage, such as tactical athletes. Future weighted-walking protocols should seek achieve higher resolution, especially near the end stage of the test where subjects reach volitional fatigue. Large increases in work rate may not be feasible at the end stages of the test.

Genomic analysis of follicular dendritic cell sarcoma by molecular inversion probe array reveals tumor suppressor-driven biology.

Follicular dendritic cell sarcoma is a rare malignant neoplasm of dendritic cell origin that is currently poorly characterized by genetic studies. To investigate whether recurrent genomic alterations may underlie the biology of follicular dendritic cell sarcoma and to identify potential contributory regions and genes, molecular inversion probe array analysis was performed on 14 independent formalin-fixed, paraffin-embedded samples. Abnormal genomic profiles were observed in 11 out of 14 (79%) cases. The majority showed extensive genomic complexity that was predominantly represented by hemizygous losses affecting multiple chromosomes. Alterations of chromosomal regions 1p (55%), 2p (55%), 3p (82%), 3q (45%), 6q (55%), 7q (73%), 8p (45%), 9p (64%), 11q (64%), 13q (91%), 14q (82%), 15q (64%), 17p (55%), 18q (64%), and 22q (55%) were recurrent across the 11 samples showing abnormal genomic profiles. Many recurrent genomic alterations in follicular dendritic cell sarcoma overlap deletions that are frequently observed across human cancers, suggesting selection, or an active role for these alterations in follicular dendritic cell sarcoma pathogenesis. In support of a tumor suppressor-driven biology, homozygous deletions involving tumor suppressor genes CDKN2A, RB1, BIRC3, and CYLD were also observed. Neither recurrent gains nor amplifications were observed. This genomic characterization provides new information regarding follicular dendritic cell sarcoma biology that may improve understanding about the underlying pathophysiology, provide better prognostication, and identify potential therapeutic markers for this rare disease.

Changes in resting mitogen-activated protein kinases following resistance exercise overreaching and overtraining.

PURPOSE: Many physiological maladaptations persist after overreaching and overtraining resistance exercise (RE). However, no studies have investigated changes in mitogen-activated protein kinases (MAPK) after overtraining in humans, despite their critical role regulating exercise-induced muscular adaptations. The purpose of this study was to describe the changes in total and resting phosphorylation status of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK) and p38-MAPK following a period of RE overreaching or overtraining. METHODS: Following 2-4 weeks of normal training (low volume/low intensity), two groups of males performed either a high-power overreaching protocol (HPOR n = 6, mean ± SD, age 23 ± 3.4 years, mass 86.5 ± 17.7 kg, height 1.77 ± 0.06 m) or high-intensity overtraining protocol (HIOT n = 8, age 19.8 ± 1.8 years, mass 76.8 ± 6.7 kg, height 1.8 ± 0.06 m). Resting muscle biopsies were obtained at baseline (BL; end of normal training period) and 24 h after the final session of stressful training (i.e., HPOR or HIOT programs). Total MAPK and ratio of phosphorylated/total (p-MAPK)- ERK1/2, JNK, and p38-MAPK were analyzed via western blotting. 2 × 2 (group × time) ANOVA determined differences in MAPK between BL and post-training protocols. RESULTS: Compared to BL, total-ERK increased after HPOR, but decreased after HIOT (p ≤ 0.05). p-ERK1/2/total-ERK increased after HIOT (p ≤ 0.05). The ratio of p-JNK/total-JNK and p-ERK1/2/total-ERK decreased after HPOR (p ≤ 0.05); however, this result was primarily due to increased total MAPK content. p-p38-MAPK decreased after HPOR (p ≤ 0.05). CONCLUSION: Total and p-MAPK are differentially expressed after HPOR and HIOT RE. These changes are likely involved in the maladaptation reported in overreaching and overtraining exercise. This is the first study describing altered MAPK in RE overtrained and overreached humans.

Do Lower-Body Dimensions and Body Composition Explain Vertical Jump Ability?

Caia, J, Weiss, LW, Chiu, LZF, Schilling, BK, Paquette, MR, and Relyea, GE. Do lower-body dimensions and body composition explain vertical jump ability? J Strength Cond Res 30(11): 3073-3083, 2016-Vertical jump (VJ) capability is integral to the level of success attained by individuals participating in numerous sport and physical activities. Knowledge of factors related to jump performance may help with talent identification and/or optimizing training prescription. Although myriad variables are likely related to VJ, this study focused on determining if various lower-body dimensions and/or body composition would explain some of the variability in performance. Selected anthropometric dimensions were obtained from 50 university students (25 men and 25 women) on 2 occasions separated by 48 or 72 hours. Estimated body fat percentage (BF%), height, body weight, hip width, pelvic width, bilateral quadriceps angle (Q-angle), and bilateral longitudinal dimensions of the feet, leg, thigh, and lower limb were obtained. Additionally, participants completed countermovement VJs. Analysis showed BF% to have the highest correlation with countermovement VJ displacement (r = -0.76, p < 0.001). When examining lower-body dimensions, right-side Q-angle displayed the strongest association with countermovement VJ displacement (r = -0.58, p < 0.001). Regression analysis revealed that 2 different pairs of variables accounted for the greatest variation (66%) in VJ: (a) BF% and sex and (b) BF% and body weight. Regression models involving BF% and lower-body dimensions explained up to 61% of the variance observed in VJ. Although the variance explained by BF% may be increased by using several lower-body dimensions, either sex identification or body weight explains comparatively more. Therefore, these data suggest that the lower-body dimensions measured herein have limited utility in explaining VJ performance.

Consistency of Lower-Body Dimensions Using Surface Landmarks and Simple Measurement Tools.

Caia, J, Weiss, LW, Chiu, LZF, Schilling, BK, and Paquette, MR. Consistency of lower-body dimensions using surface landmarks and simple measurement tools. J Strength Cond Res 30(9): 2600-2608, 2016-Body dimensions may influence various types of physical performance. This study was designed to establish the reliability and precision of bilateral lower-body dimensions using surface anatomic landmarks and either sliding calipers or goniometry. Fifty university students (25 men and 25 women) were measured on 2 separate occasions separated by 48 or 72 hours. A small digital caliper was used to acquire longitudinal dimensions of the feet, whereas a larger broad-blade caliper was used to measure lower-limb, hip, and pelvic dimensions. Quadriceps angle (Q-angle) was determined through surface goniometry. Data for all foot and lower-limb dimensions were both reliable and precise (intraclass correlation coefficient (ICC) ≥0.72, SEM 0.1-0.5 cm). Measures of Q-angle were also reliable and precise (ICC ≥0.85, SEM 0.2-0.4°). Findings from this investigation demonstrate that lower-body dimensions may be reliably and precisely measured through simple practical tests, when surface anatomic landmarks and standardized procedures are used. Although intertester reliability remains to be established, meticulous adherence to specific measurement protocols is likely to yield viable output for lower-body dimensions when more sophisticated methods are unavailable or inappropriate.

Self-Reported Physical Tasks and Exercise Training in Special Weapons and Tactics (SWAT) Teams.

Davis, MR, Easter, RL, Carlock, JM, Weiss, LW, Longo, EA, Smith, LM, Dawes, JJ, and Schilling, BK. Self-reported physical tasks and exercise training in Special Weapons and Tactics (SWAT) teams. J Strength Cond Res 30(11): 3242-3248, 2016-Little research has been done examining the most physically demanding tasks a SWAT officer may perform in the line of duty. Our objective was to analyze the rankings of tasks by SWAT officers based on frequency, difficulty, and importance and assess if training is addressing traits needed for successful task completion. A survey was designed using Qualtrics (Qualtrics Labs Inc). The survey had a demographics section, performance section, and training section. Officers were contacted by phone or e-mail and asked about interest in participating. Officers who agreed were sent the survey. Our results found a strong correlation between frequency of task and importance (r = 0.69, p = 0.001), and a moderate correlation was found between task difficulty and importance (r = 0.37, p = 0.005). Task rankings were averaged across the 3 domains to assess "overall" importance, and the top 3 tasks were assessed for necessary traits for successful performance. Power and strength were determined to be the most important traits for successful performance. Officers ranked the top 2 focuses of their training program in the training section as stamina/muscular endurance and cardiovascular/respiratory endurance. Training programs for SWAT officers should be developed to improve performance of the tasks with the highest "overall" importance. Therefore, a training program should emphasize strength and power improvements while not neglecting other measures of fitness.

Piwi-Interacting RNAs (piRNAs) Are Dysregulated in Renal Cell Carcinoma and Associated with Tumor Metastasis and Cancer-Specific Survival.

Piwi-interacting RNAs (piRNAs) are a distinct group of small noncoding RNAs (sncRNAs) that silence transposable genetic elements to protect genome integrity. Because of their limited expression in gonads and sequence diversity, piRNAs remain the most mysterious class of small RNAs. Studies have shown piRNAs are present in somatic cells and dysregulated in gastric, breast and liver cancers. By deep sequencing 24 frozen benign kidney and clear cell renal cell carcinoma (ccRCC) specimens and using the publically available piRNA database, we found 26,991 piRNAs present in human kidney tissue. Among 920 piRNAs that had at least two copies in one specimen, 19 were differentially expressed in benign kidney and ccRCC tissues, and 46 were associated with metastasis. Among the metastasis-related piRNAs, we found three piRNAs (piR-32051, piR-39894 and piR-43607) to be derived from the same piRNA cluster at chromosome 17. We confirmed the three selected piRNAs not to be miRNAs or miRNA-like sncRNAs. We further validated the aberrant expression of the three piRNAs in a 68-case formalin-fixed and paraffin-embedded (FFPE) ccRCC tissue cohort and showed the up-regulation of the three piRNAs to be highly associated with ccRCC metastasis, late clinical stage and poor cancer-specific survival.

Cytotoxic Molecule-positive Epstein-Barr Virus-associated Peripheral T-cell Lymphoma in a 20-Month-old Child: A Case Report and Review of the Literature.

Peripheral T-cell lymphoma (PTCL) is rare in children. Expression of cytotoxic molecules (CM) in nodal PTCL has unique clinicopathologic features, including an Epstein-Barr virus (EBV) association. However, CM+, EBV-associated PTCL is extremely rare in the childhood, with only 1 study having been reported to date, including both pediatric and adult patients. We report a case of CM+ PTCL in a 20-month-old boy with left neck lymphadenopathy as well as multiple visceral lesions. A biopsied lymph node was diffusely infiltrated by atypical lymphoid cells with a CD4/CD8, granzyme B+, perforin+, and TIA-1+ phenotype, and EBV positivity by in situ hybridization. Rearrangements of the TCR γ-chain and ß-chain genes were demonstrated by polymerase chain reaction. Ancillary genetic studies detected trisomy 2, trisomy 10, a structurally abnormal 6p, and additional copies of the IRF4 gene. Multiple bone marrow biopsies failed to show any evidence of tumor, histiocytic hyperplasia, or hemophagocytosis. This lesion was therefore diagnosed as "CM+, EBV-associated high-grade peripheral T-cell lymphoma." After 5 cycles of chemotherapy, the patient was in remission 8 months following initial diagnosis. To our knowledge, this represents the youngest child with this rare tumor in the published literature, and showing an unusually favorable initial response to therapy.

Distinctive immunohistochemical staining in littoral cell angioma using ERG and WT-1.

Littoral cell angioma (LCA) is a rare vascular tumor of the spleen. It has an immunohistochemical staining pattern that is somewhat distinctive but can still be occasionally confused with other vascular and stromal proliferations in the spleen. In this study, LCA was evaluated using Ets-related gene (ERG) and Wilms tumor-1 (WT-1), relatively recently described vascular markers. In addition, other vascular lesions including normal spleen, hemangiomas, hamartoma, peliosis, and sclerosing angiomatoid nodular transformation were evaluated using these stains. In LCA, ERG stains the endothelial cells of the tumor as expected. ERG also was uniformly positive in vascular elements of other lesions except peliosis. However, in contrast to most other vascular elements, LCA was negative for WT-1 staining. This staining pattern may prove useful in diagnosing LCA and may provide insight into the derivation of the distinctive tumor.

Evidence of BRAF V600E in indeterminate cell tumor and interdigitating dendritic cell sarcoma.

BRAF V600E mutations have been reported in several histiocytic and dendritic cell neoplasms. In this case series, we report BRAF V600E-positive histiocytic and dendritic cell neoplasms in association with lymphomas and lymphoid proliferations. This is a review of cases with immunohistochemistry for BRAF V600E, with additional immunohistochemistry to categorize tumors. We report the first case of BRAF V600E-positive indeterminate cell tumor in association with angioimmunoblastic T-cell lymphoma. We also report a case of BRAF V600E-positive interdigitating dendritic cell sarcoma in a patient with positive B-cell polymerase chain reaction. It is unclear if these neoplasms developed as transdifferentiation of lymphoid neoplasms or if they developed independently. These cases illustrate the expanding spectrum of BRAF V600E-positive histiocytic and dendritic cell tumors and suggest that attention should be paid to lymphomas for possible coincident presentation of these disorders.

Effects of footwear condition on maximal jumping performance.

The purpose of this investigation was to examine the effects of footwear on kinetics and lower extremity electromyographic (EMG) activity during the vertical jump (VJ) and standing long jump. Fifteen men performed the 2 jump types in 3 footwear conditions: barefoot, minimal shoes, and cross-training shoes. Jump displacement and kinetic data were collected, along with EMG activity of the biceps femoris, medial gastrocnemius, peroneus longus, semitendinosus/semimembranosus, soleus (SOL), tibialis anterior, vastus lateralis, and vastus medialis. Subjective footwear performance and comfort were also assessed with a custom survey. No differences were found in jump displacement, peak ground reaction forces (GRF), countermovement and propulsive phase durations, vertical impulse, peak countermovement, or average propulsive EMG activity. Significant differences in peak propulsive root mean square EMG were found between barefoot and minimal shoes (p = 0.030) and minimal shoes and shod (p = 0.031) conditions for the SOL during the VJ, and for average countermovement EMG of the semitendinosus/semimembranosus during the VJ between barefoot and shod (p = 0.039). Moderate-to-large effect sizes (>0.59) were found between conditions for horizontal GRF, propulsive phase duration, average EMG amplitude, and duration of EMG activity during the countermovement. Participants reported higher comfort ratings when shod compared with barefoot and minimal shoes for both jumps. Participants also perceived better performance when shod compared with barefoot and minimal shoes for the VJ only. No acute differences in displacement were observed between barefoot, minimal shoes, and cross-trainer shoes during vertical and horizontal jumps. Some differences in muscle activation and timing seem to be present, and thus, training effects between footwear conditions should be examined. Footwear familiarization may prove beneficial, as acute increases in comfort seem unrelated to performance improvements.

Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart.

Rare cases of Merkel cell carcinoma have been encountered in lymph nodes with unknown extranodal primary, which exhibit similar morphologic and immunophenotypic features to those in primary cutaneous Merkel cell carcinomas. However, it is uncertain whether the nodal Merkel cell carcinoma is a primary tumor of the lymph node or represents a metastasis from an occult or regressed extranodal lesion. To establish an accurate diagnosis of the nodal Merkel cell carcinoma can be challenging because of significant morphologic mimics, including lymphoblastic lymphoma and metastatic small cell carcinoma. Moreover, there is no consensus for a diagnostic term, and many different terms have been used, which can be confusing and may not fully reflect the nature of nodal Merkel cell carcinoma. In this study, we investigated the detailed clinicopathologic features of 22 nodal Merkel cell carcinomas, with comparison to 763 primary cutaneous cases retrieved from the literature. Overall, the nodal and cutaneous Merkel cell carcinomas shared similar clinical presentations, morphologic spectrum, and immunophenotype; both were mostly seen in elderly male with a typical neuroendocrine morphology. Most of cases expressed CK20, synaptophysin, and chromogranin A; and PAX5 and TdT were also positive in majority of cases. However, nodal Merkel cell carcinomas had a significantly lower association with Merkel cell polyomavirus than cutaneous cases (31% vs 76%, P=0.001). Therefore, these two entities may arise from overlapping but not identical biological pathways. We also recommend the use of the diagnostic term 'Merkel cell carcinoma of lymph node' to replace many other names used.

S1PR1 is an effective target to block STAT3 signaling in activated B cell-like diffuse large B-cell lymphoma.

STAT3 plays a crucial role in promoting progression of human cancers, including several types of B-cell lymphoma. However, as a transcription factor lacking its own enzymatic activity, STAT3 remains difficult to target with small-molecule drugs in the clinic. Here we demonstrate that persistent activated STAT3 colocalizes with elevated expression of S1PR1, a G-protein-coupled receptor for sphingosine-1-phosphate (S1P), in the tumor cells of the activated B cell-like subtype of diffuse large B-cell lymphoma patient specimens. Inhibition of S1PR1 expression by shRNA in the lymphoma cells validates that blocking S1PR1 affects expression of STAT3 downstream genes critically involved in tumor cell survival, proliferation, tumor invasion, and/or immunosuppression. Using S1PR1 shRNA, or FTY720, an antagonist of S1P that is in the clinic for other indications, we show that inhibiting S1PR1 expression down-regulates STAT3 activity and causes growth inhibition of the lymphoma tumor cells in vitro and in vivo. Our results suggest that targeting S1P/S1PR1 using a clinically relevant and available drug or other approaches is potentially an effective new therapeutic modality for treating the activated B cell-like subtype of diffuse large B-cell lymphoma, a subset of lymphoma that is less responsive to current available therapies.

A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32.

Nodular sclerosing Hodgkin lymphoma (NSHL) is a distinct, highly heritable Hodgkin lymphoma subtype. We undertook a genome-wide meta-analysis of 393 European-origin adolescent/young adult NSHL patients and 3315 controls using the Illumina Human610-Quad Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We identified 3 single nucleotide polymorphisms (SNPs) on chromosome 6p21.32 that were significantly associated with NSHL risk: rs9268542 (P = 5.35 × 10(-10)), rs204999 (P = 1.44 × 10(-9)), and rs2858870 (P = 1.69 × 10(-8)). We also confirmed a previously reported association in the same region, rs6903608 (P = 3.52 × 10(-10)). rs204999 and rs2858870 were weakly correlated (r(2) = 0.257), and the remaining pairs of SNPs were not correlated (r(2) < 0.1). In an independent set of 113 NSHL cases and 214 controls, 2 SNPs were significantly associated with NSHL and a third showed a comparable odds ratio (OR). These SNPs are found on 2 haplotypes associated with NSHL risk (rs204999-rs9268528-rs9268542-rs6903608-rs2858870; AGGCT, OR = 1.7, P = 1.71 × 10(-6); GAATC, OR = 0.4, P = 1.16 × 10(-4)). All individuals with the GAATC haplotype also carried the HLA class II DRB1*0701 allele. In a separate analysis, the DRB1*0701 allele was associated with a decreased risk of NSHL (OR = 0.5, 95% confidence interval = 0.4, 0.7). These data support the importance of the HLA class II region in NSHL etiology.