Inclusion of Histopathology in Dose Range-Finding Nonclinical Studies for Inhaled Drug Products.

Drug development is a lengthy process that promotes and protects the health and safety of future patients. Nonclinical safety studies follow essentially similar designs that fulfill regulatory requirements but are amended based on factors including the mechanism of action, class of molecule, and route of administration. Clinical observations, clinical pathology, and macroscopic pathology in dose range-finding (DRF) studies generally provide sufficient information to select doses for pivotal studies by most delivery routes.

Precision Oncology and Systemic Targeted Therapy in Pseudomyxoma Peritonei.

Purpose: Pseudomyxoma peritonei (PMP) is a rare and poorly understood malignant condition characterized by the accumulation of intra-abdominal mucin produced from peritoneal metastases. Currently, cytoreductive surgery remains the mainstay of treatment but disease recurrence and death after relapse frequently occur in patients with PMP. New therapeutic strategies are therefore urgently needed for these patients.

A consulting room with a view: Psychotherapy and the ecological context.

Background: The field of psychotherapy is witnessing a lively debate today. The literature on the efficacy of psychological interventions has grown exponentially, but the assumptions of the prevailing research paradigms have been criticised from many points of view. One of the main concerns is that of a too often simplistic conception of psychotherapy, viewed as a set of specific methods for the treatment of point-like problems or symptoms.

Interpreting life-history traits, seasonal cycles, and coastal climate from an intertidal mussel species: Insights from 9000 years of synthesized stable isotope data.

Understanding past coastal variability is valuable for contextualizing modern changes in coastal settings, yet existing Holocene paleoceanographic records for the North American Pacific Coast commonly originate from offshore marine sediments and may not represent the dynamic coastal environment. A potential archive of eastern Pacific Coast environmental variability is the intertidal mussel species Mytilus californianus. Archaeologists have collected copious stable isotopic (δ18O and δ13C) data from M.

Rest-activity rhythm disruption and metabolic health in schizophrenia: a cross-sectional actigraphy study of community-dwelling people living with schizophrenia and nonpsychiatric comparison participants.

Study Objectives: People living with schizophrenia (PLWS) have increased physical comorbidities and premature mortality which may be linked to dysregulated rest-activity rhythms (RARs). This study aimed to compare RARs between PLWS and nonpsychiatric comparison participants (NCs) and to examine the relationships of RARs with age, sleep, metabolic, and physical health outcomes and, among PLWS, relationships of RARs with illness-related factors.

Methods: The study sample included 26 PLWS and 36 NCs, assessed with wrist-worn actigraphy to compute RAR variables and general sleep variables.

DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype.

Tumor relapse is linked to rapid chemoresistance and represents a bottleneck for cancer therapy success. Engagement of a reduced proliferation state is a non-mutational mechanism exploited by cancer cells to bypass therapy-induced cell death. Through combining functional pulse-chase experiments in engineered cells and transcriptomic analyses, we identify DPPA3 as a master regulator of slow-cycling and chemoresistant phenotype in colorectal cancer (CRC).

Proopiomelanocortin (POMC) and psychodermatology.

Psychodermatology is the crossover discipline between Dermatology and Clinical Psychology and/or Psychiatry. It encompasses both Psychiatric diseases that present with cutaneous manifestations (such as delusional infestation) or more commonly, the psychiatric or psychological problems associated with skin disease, such as depression associated with psoriasis. These problems may be the result either of imbalance in or be the consequence of alteration in the homoeostatic endocrine mechanisms found in the systemic hypothalamic-pituitary-adrenal axis or in the local cutaneous corticotrophin-releasing factor-proopiomelanocortin-corticosteroid axis.

Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer.

Background: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics.

Materials And Methods: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs.

Orthotopic Implantation of Patient-Derived Cancer Cells in Mice Recapitulates Advanced Colorectal Cancer.

Over the last decade, more sophisticated preclinical colorectal cancer (CRC) models have been established using patient-derived cancer cells and 3D tumoroids. Since patient derived tumor organoids can retain the characteristics of the original tumor, these reliable preclinical models enable cancer drug screening and the study of drug resistance mechanisms. However, CRC related death in patients is mostly associated with the presence of metastatic disease.

Cannabidiol Decreases Intestinal Inflammation in the Ovariectomized Murine Model of Postmenopause.

Cannabidiol (CBD) (25 mg/kg peroral) treatment was shown to improve metabolic outcomes in ovariectomized (OVX) mice deficient in 17β-estradiol (E2). Herein, CBD effects on intestinal and hepatic bile acids (BAs) and inflammation were investigated. Following RNA sequencing of colon tissues from vehicle (VEH)- or CBD-treated sham surgery (SS) or OVX mice ( = 4 per group), differentially expressed genes (DEGs) were sorted in ShinyGO.

Phosphorylation/dephosphorylation of PTP-PEST at Serine 39 is crucial for cell migration.

We investigated the molecular details of the role of protein tyrosine phosphatase (PTP)-PEST in cell migration. PTP-PEST knockout mouse embryonic fibroblasts (KO MEFs) and MEF cells expressing a dominant-negative mutant of PTP-PEST showed significant suppression of cell migration compared to MEF cells expressing wild-type PTP-PEST (WT MEFs). Moreover, MEF cells harbouring a constitutively active mutant of PTP-PEST (S39A MEFs) showed a marked decrease in cell migration.

A Label Retaining System to Capture Slow-Cycling Cancer Cells.

Dormant or slow-cycling tumor cells can form a residual chemoresistant reservoir responsible for relapse in patients, years after curative surgery and adjuvant therapy. Slow-cycling cancer cells (SCCC) represent a cellular status rather than a cell population present in a minor proportion, even in growing tumors. We have adapted the pulse-chase expression of histone H2B fused to enhanced GFP (H2BeGFP) for labelling and isolating SCCC.

Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors.

Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than 500 therapeutic bAbs generated against Wingless-related integration site (WNT) and receptor tyrosine kinase (RTK) targets were functionally evaluated by high-content imaging to capture the complexity of PDO responses.

Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer.

Androgen receptor (AR)-castrate-resistant prostate cancer (CRPC) is an aggressive form of prostate cancer that does not have clinically approved targeted treatment options. To this end, the cytotoxic potential of raloxifene and the synthetic curcumin derivative 2,6-bis (pyridin-4-ylmethylene)-cyclohexanone (RL91) was examined in AR-(PC3 and DU145) cells and AR+ (LnCaP) CRPC cells. The results showed that both raloxifene and RL91 elicited significant cytotoxicity across three cell lines with the lowest EC values in PC3 cells.

Spatial Analysis of Chinese American Ethnic Enclaves and Community Health Indicators in New York City.

In New York City, the population of Chinese Americans has grown faster than that of any other minority racial/ethnic group, and now this community constitutes almost half of all Chinese Americans living in the northeastern United States. Nonetheless, scant research attention has been given to Chinese American ethnic enclaves and little is known about the health status of their residents. This study aims to help address this gap in the literature by: (1) improving our understanding of the spatial settlement of Chinese Americans living in New York City from 2000 to 2016; and (2) assessing associations between a New York City resident's likelihood of living in a Chinese American enclave and their access to health care and perceived health status, two measures of community health.

Developing an agent-based model of oral healthcare utilization by Chinese Americans in New York City.

Many Chinese Americans experience certain barriers (e.g., low income, English as a second language, lack of insurance, cultural differences, discrimination) when they seek oral healthcare services.

Network-based rTMS to modulate working memory: The difficult choice of effective parameters for online interventions.

Background: Online repetitive transcranialmagnetic stimulation (rTMS) has been shown to modulate working memory (WM) performance in a site-specific manner, with behavioral improvements due to stimulation of the dorsolateral prefrontal cortex (DLPFC), and impairment from stimulation to the lateral parietal cortex (LPC). Neurobehavioral studies have demonstrated that subprocesses of WM allowing for the maintenance and manipulation of information in the mind involve unique cortical networks. Despite promising evidence of modulatory effects of rTMS on WM, no studies have yet demonstrated distinct modulatory control of these two subprocesses.

Real-World Outcomes in Diabetic Macular Edema for the 0.2 µg/Day Fluocinolone Acetonide Implant: Case Series from the Midlands, UK.

Aim: To investigate real-world effectiveness and safety of fluocinolone acetonide (FAc) implant over three years of treatment in eyes with diabetic macular edema (DME) in a population with large ethnic diversity.

Methods: This audit of three large treatment centres in the UK involved retrospective collection of outcome data (best recorded visual acuity [BRVA] by Early Treatment Diabetic Retinopathy Study [ETDRS] letters, central retinal thickness [CRT], intraocular pressure [IOP] and use of supplementary treatments) from patients with DME treated with 0.2 µg/day FAc intravitreal implant with three-year follow-up expected.

Developing Expert Gaze Pattern in Laparoscopic Surgery Requires More than Behavioral Training.

Expertise in laparoscopic surgery is realized through both manual dexterity and efficient eye movement patterns, creating opportunities to use gaze information in the educational process. To better understand how expert gaze behaviors are acquired through deliberate practice of technical skills, three surgeons were assessed and five novices were trained and assessed in a 5-visit protocol on the Fundamentals of Laparoscopic Surgery peg transfer task. The task was adjusted to have a fixed action sequence to allow recordings of dwell durations based on pre-defined areas of interest (AOIs).

Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway.

Aberrant Wnt signaling drives a number of cancers through regulation of diverse downstream pathways. Wnt/β-catenin signaling achieves this in part by increasing the expression of proto-oncogenes such as and cyclins. However, global assessment of the Wnt-regulated transcriptome in genetically distinct cancers demonstrates that Wnt signaling suppresses the expression of as many genes as it activates.

Movement form of the overarm throw for children at 6, 10 and 14 years of age.

This study investigated overarm throwing technique at different developmental ages in children from the perspective of three distinct, though potentially complementary, approaches to motor skill acquisition. Children at 6, 10, and 14 years of age ( = 18), completed dominant overarm throws during which whole-body kinematic data were collected. Firstly, application of Newell's ([1985].

Extensive morphological variability in asexually produced planktic foraminifera.

Marine protists are integral to the structure and function of pelagic ecosystems and marine carbon cycling, with rhizarian biomass alone accounting for more than half of all mesozooplankton in the oligotrophic oceans. Yet, understanding how their environment shapes diversity within species and across taxa is limited by a paucity of observations of heritability and life history. Here, we present observations of asexual reproduction, morphologic plasticity, and ontogeny in the planktic foraminifer in laboratory culture.