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Protocadherin‑8 (PCDH8) is a member of the protocadherin subfamily within the cadherin superfamily of cell adhesion molecules. PCDH8 is silenced in a variety of solid tumors including those of the breast, and believed to be a tumor suppressor. Here we show that PCDH8 is suppressed by estrogen in MCF-7 and T47D breast cancer cells. The suppression is dependent on estrogen receptor‑α (ERα) expression. Knockdown of ERα alone induces the expression of PCDH8. The inverse correlation between PCDH8 and ERα expression is also apparent from the analysis of PCDH8 expression in breast tumors from the TCGA-BRCA dataset. Since estrogen produces mitogenic effects in ERα positive breast cancer cells, estrogen-mediated suppression of PCDH8 is consistent with its purported tumor suppressor function. Functional studies on PCDH8 in breast cancer cells may yield valuable insights into the mechanisms of estrogen-mediated epithelial-mesenchymal transition.

Fine-grained action recognition involves comparison of similar actions of variable-length size consisting of subtle interactions between human and specific objects. Hence, we propose a dynamic kernel-based approach to handle the variable-length patterns for effective recognition of fine-grained actions. Initially, we extract local spatio-temporal features for each video to capture appearance and motion information effectively. An action-independent Gaussian mixture model (AIGMM) is trained on the extracted features of all fine-grained actions to analyze spatio-temporal information and preserve the local similarities among fine-grained actions. Then, the statistics of AIGMM, namely, mean, covariance, and posteriors are used to build the kernels for finding the similarity between any two fine-grained actions by mapping statistics to kernel feature space. We demonstrate the effectiveness of proposed approach using three dynamic kernels i.e., GMM mean interval kernel, supervector kernel, intermediate matching kernel on four varieties of fine-grained action datasets, namely, MERL, JIGSAWS, KSCGR, and MPII cooking2

Targeted drug delivery has been the major topic in drug formulation and delivery. As nanomedicine emerges to create nano scale therapeutics and diagnostics, it is still essential to embed targeting capability to these novel systems to make them useful. Here we discuss various targeting approaches for delivery of therapeutic and diagnostic nano materials in view of search for more universal methods to target diseased tissues. Many diseases are accompanied with hypoxia and acidosis. Coating nanoparticles with pH Low Insertion Peptides (pHLIPs) increases efficiency of targeting acidic diseased tissues. It has been showing promising results to create future nanotheranostics for cancer and other diseases which are dominating in the present world.

Summary Background Lenalidomide plus dexamethasone is a reference treatment for patients with newly diagnosed myeloma. The combination of the proteasome inhibitor bortezomib with lenalidomide and dexamethasone has shown significant efficacy in the setting of newly diagnosed myeloma. We aimed to study whether the addition of bortezomib to lenalidomide and dexamethasone would improve progression-free survival and provide better response rates in patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant. Methods In this randomised, open-label, phase 3 trial, we recruited patients with newly diagnosed multiple myeloma aged 18 years and older from participating Southwest Oncology Group (SWOG) and National Clinical Trial Network (NCTN) institutions (both inpatient and outpatient settings). Key inclusion criteria were presence of CRAB (C=calcium elevation; R=renal impairment; A=anaemia; B=bone involvement) criteria with measurable disease (measured by assessment of free light chains), Eastern Cooperative Oncology Group (ECOG) performance status of 0–3, haemoglobin concentration 9 g/dL or higher, absolute neutrophil count 1 × 10 3 cells per mm 3 or higher, and a platelet count of 80 000/mm 3 or higher. We randomly assigned (1:1) patients to receive either an initial treatment of bortezomib with lenalidomide and dexamethasone (VRd group) or lenalidomide and dexamethasone alone (Rd group). Randomisation was stratified based on International Staging System stage (I, II, or III) and intent to transplant (yes vs no). The VRd regimen was given as eight 21-day cycles. Bortezomib was given at 1·3 mg/m 2 intravenously on days 1, 4, 8, and 11, combined with oral lenalidomide 25 mg daily on days 1–14 plus oral dexamethasone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regimen was given as six 28-day cycles. The standard Rd regimen consisted of 25 mg oral lenalidomide once a day for days 1–21 plus 40 mg oral dexamethasone once a day on days 1, 8, 15, and 22. The primary endpoint was progression-free survival using a prespecified one-sided stratified log rank test at a significance level of 0·02. Analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00644228. Findings Between April, 2008, and February, 2012, we randomly assigned 525 patients at 139 participating institutions (264 to VRd and 261 to Rd). In the randomly assigned patients, 21 patients in the VRd group and 31 in the Rd group were deemed ineligible based mainly on missing, insufficient, or early or late baseline laboratory data. Median progression-free survival was significantly improved in the VRd group (43 months vs 30 months in the Rd group; stratified hazard ratio [HR] 0·712, 96% CI 0·56–0·906; one-sided p value 0·0018). The median overall survival was also significantly improved in the VRd group (75 months vs 64 months in the Rd group, HR 0·709, 95% CI 0·524–0·959; two-sided p value 0·025). The rates of overall response (partial response or better) were 82% (176/216) in the VRd group and 72% (153/214) in the Rd group, and 16% (34/216) and 8% (18/214) of patients who were assessable for response in these respective groups had a complete response or better. Adverse events of grade 3 or higher were reported in 198 (82%) of 241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group; 55 (23%) and 22 (10%) patients discontinued induction treatment because of adverse events, respectively. There were no treatment-related deaths in the Rd group, and two in the VRd group. Interpretation In patients with newly diagnosed myeloma, the addition of bortezomib to lenalidomide and dexamethasone resulted in significantly improved progression-free and overall survival and had an acceptable risk-benefit profile. Funding NIH, NCI, NCTN, Millennium Pharmaceuticals, Takeda Oncology Company, and Celgene Corporation.

Human action recognition using pose-based features is proposed.Use of key movements of actions for efficient input representation.Unsupervised pre-training using stacked auto encoder is exploited. Display Omitted In this paper, we propose a method for classification of human actions using pose based features. We demonstrate that statistical information of key movements of actions can be utilized in designing an efficient input representation, using fuzzy membership functions. The ability of stacked auto encoder to learn the underlying features of input data is exploited to recognize human actions. The efficacy of the proposed approach is demonstrated on CMU MOCAP and Berkeley MHAD datasets.

Background & Aim Since numbers of harvested hematopoietic stem cells (HSCs) continues to limit not only laboratory research but also clinical HSC transplantation and gene therapies, development of ex vivo culture systems to expand harvested human hematopoietic stem-progenitor cells (HSPCs) remains a critical translational research quest. To address the barrier that HSCs generally die or differentiate in current ex vivo culture media, we have developed an xeno-free, serum-free medium - StemPro™ HSC Expansion Medium (Prototype) by extensive evaluation of iterative modification of medium constituents. Methods, Results & Conclusion Cultures of primary human CD34+ HSPCs immunopurified from cord blood, mobilized peripheral blood and bone marrow harvests generated greatly increased numbers of immunphenotyped-defined HSPC in StemPro™ HSC Expansion Medium (Prototype) supplemented with FLT3L, KITL (also known as SCF), TPO, IL-3, and IL-6 (FKT36), as compared to either uncultured day 0 cells or cells cultured in industry-standard culture media containing FKT36. For example, culture of primary human CD34+ cells from mobilized peripheral blood for 7 days in FKT36-containing StemPro™ HSC Expansion Medium (Prototype) resulted in ∼100-fold increased numbers of CD34+CD45+Lin− cells and ∼2000-fold increased numbers of CD34+Lin−CD90+CD45RA− cells (an early HSPC immunophenotype), as compared to uncultured day 0 cells. The ex vivo-cultured cells contained high frequencies of aldehyde dehydrogenase-containing cells and formed erythroid and non-erythroid hematopoietic colonies in vitro. In an ongoing in vivo hematopoietic chimera experiment, ex vivo-cultured mPB CD34+ HSPCs harbored robust in vivo-engrafting capacity at the 8-week post-transplant short-term HSC time point evaluated to date. Thus, it appears that StemPro™ HSC Expansion Medium (Prototype) supports superior HSPC expansion that includes self-renewal of short-term-HSCs. Evaluation of long-term-HSC capacity is in progress.

The unscheduled arrest of DNA replication forks is a frequent and mutagenic phenomenonaffecting all growing cells. DNA-bound proteins and elongating transcription complexes are thetwo major triggers of unscheduled fork arrest, and it is generally thought that these effectsoperate by physical occlusion. We show here that, instead, replication fork arrest results from theaccumulation of superhelical stress between the fork and barrier, thousands of base pairs away.Reducing positive supercoiling prevented fork arrest, allowing fork progression through both astable protein complex and a highly transcribed site oriented toward oncoming replication forks.Reducing positive supercoiling improved fork progression globally and decreased the occurrenceof spontaneous fork stalling, indicating that spontaneous fork blockages are frequent and alsosupercoiling-mediated. These results transform our understanding of how DNA-bound obstaclesimpede replication forks — by restricting the passage of inhibitory supercoiling instead of bydirect collision.

Although it has been recognized for several decades that chromosome structure regulates the capacity of replication origins to initiate, very little is known about how or if cells actively regulate structure to direct initiation [1–3]. We report that a localized inducible protein tether between the chromosome and cell membrane in E. coli cells imparts a rapid and complete block to replication initiation. Tethers, composed of a trans-membrane and transcription repressor fusion protein bound to an array of operator sequences, can be placed up to one megabase from the origin with no loss of penetrance. Tether-induced initiation blocking has no effect on elongation at pre-existing replication forks and does not cause cell or DNA damage. Whole-genome and site-specific fluorescent DNA labeling in tethered cells indicates that global nucleoid structure and chromosome organization are disrupted. Gene expression patterns, assayed by RNA sequencing shows that tethering induces global supercoiling changes, which are likely incompatible with replication initiation. Parallels between tether-induced initiation blocking and rifampicin treatment, and the role of programmed changes in chromosome structure in replication control are discussed.

It is unknown whether radiation safety practices that minimize radiation doses are uniformly applied across all institutions performing percutaneous coronary intervention (PCI). This study was performed to evaluate the institutional variability in high radiation doses administered during PCI in the