Hot-wiring dynein-2 establishes roles for IFT-A in retrograde train assembly and motility.

Intraflagellar transport (IFT) trains, built around IFT-A and IFT-B complexes, are carried by opposing motors to import and export ciliary cargo. While transported by kinesin-2 on anterograde IFT trains, the dynein-2 motor adopts an autoinhibitory conformation until it needs to be activated at the ciliary tip to power retrograde IFT. Growing evidence has linked the IFT-A complex to retrograde IFT; however, its roles in this process remain unknown. Here, we use CRISPR-Cas9-mediated genome editing to disable the dynein-2 autoinhibition mechanism in Caenorhabditis elegans and assess its impact on IFT with high-resolution live imaging and photobleaching analyses. Remarkably, this dynein-2 "hot-wiring" approach reignites retrograde motility inside IFT-A-deficient cilia without triggering tug-of-war events. In addition to providing functional evidence that multiple mechanisms maintain dynein-2 inhibited during anterograde IFT, our data establish key roles for IFT-A in mediating motor-train coupling during IFT turnaround, promoting retrograde IFT initiation, and modulating dynein-2 retrograde motility.

Gellan gum-based hydrogels support the recreation of the dermal papilla microenvironment.

The dermal papilla (DP), a specialized compartment within the hair follicle, regulates hair growth. However, human DP cells rapidly lose their inductivity in 2D-culture given the loss of positional and microenvironmental cues. Spheroids have been capable of recreating the 3D intercellular organization of DP cells, however, DP cell-matrix interactions are poorly represented. Considering the specific nature of the DP's extracellular matrix (ECM), we functionalized gellan gum (GG) with collagen IV-(HepIII) or fibronectin-(cRGDfC) derived peptide sequences to generate a 3D environment in which the phenotype and physiological functions of DP cells are restored. We further tuned the stiffness of the microenvironments by varying GG amount. Biomimetic peptides in stiffer hydrogels promoted the adhesion of DP cells, while each peptide and amount of polymer independently influenced the type and quantity of ECM proteins deposited. Furthermore, although peptides did not seem to have an influence, stiffer hydrogels improved the inductive capacity of DP cells after short term culture. Interestingly, independently of the peptide, these hydrogels supported the recapitulation of basic hair morphogenesis-like events when incorporated in an organotypic human skin in vitro model. Our work demonstrates that tailored GG hydrogels support the generation of a microenvironment in which both cell-ECM and cell-cell interactions positively influence DP cells towards the creation of an artificial DP.

[Gastric metastases with a choriocarcinoma component from a postpuberal teratoma with mature histology]. / Metástasis gástricas con componente de coriocarcinoma de un teratoma testicular pospuberal con histología madura.

Germ cell tumors are the most frequent neoplasia in young males. The aims of this study is to describe a case in which a postpuberal teratoma suffers a transformation to choriocarcinoma and metastasize to stomach. We have made a systematic review in PubMed and consensus documents to study this mismatch between the tumour, metastasis and the exception of gastric metastatic affectation. We describe three options to explain this discordance: a mixed germ cells tumour, a burned out tumour or a germ cells tumour derived from a malignant germ cell tumour precursor or different clonal strains. After made a thorough investigation we conclude that the most truly option is the last one as we extensive explain below. Once the gastric metastatic lesions are extremely rare and reach to <5%, but there are not conclusive assessments.

Dignity and psychosocial related variables in elderly advanced cancer patients.

INTRODUCTION: Most cancers occur in older individuals, who are more vulnerable due to functional impairment, multiple comorbidities, cognitive impairment, and lack of socio-familial support. These can undermine patients' sense of dignity. This study seeks to compare dignity scores in older patients with advanced cancer on sociodemographic and clinical variables and analyze the predictive value of anxiety, depression, functional limitations, and social support on dignity scores. METHODS: A prospective, multicenter, observational study conducted with participation of 15 hospitals in Spain from February 2020 to October 2021. Patients with newly-diagnosed, advanced cancer completed the dignity (PPDS), anxiety and depression (BSI), Social Support (Duke-UNC-11), and functional limitations (EORTC-C30) scales. Lineal regression analyses explored the effects of anxiety, depression, functional status, and social support on dignity, adjusting for sociodemographic and clinical variables. RESULTS: A total of 180 subjects participated in this study. The results of the correlation analysis revealed that dignity correlated negatively with anxiety, depression, and sex, and positively with social support, functional status, and longer estimated survival. Thus, women, and more anxious and depressed individuals scored lower on the dignity scale, whereas patients with more social support, fewer functional limitations, and longer estimated survival scored higher. CONCLUSION: In conclusion, being female, having a lower educational level, lower estimated survival, depression, anxiety, less social support, and limited functionality are correlated with less dignity in the elderly with advanced cancer. It is a priority to manage both physical and psychological symptoms in patients with unresectable advanced cancer to mitigate psychological distress and increase their sense of dignity.

Resilience, Social Support, and Anxious Preoccupation in Patients with Advanced Cancer during COVID-19 Pandemic.

This study examines the mediating role of social support between anxious preoccupation and resilience in patients with cancer during COVID-19. NEOetic_SEOM is a prospective, multicenter study involving individuals with advanced, unresectable cancer who completed the following scales: Resilience (BCRS), Social Support (Duke-UNC-11), and anxious preoccupation subscale of the Mini-Mental Adjustment to Cancer (M-MAC) before starting antineoplastic treatment. Between March 2020 and July 2021, 507 patients (55% male; mean age, 65) were recruited. No differences in resilience were observed based on sociodemographic or clinical characteristics. Social support in people with advanced, unresectable cancer promotes both decreased anxious preoccupation and greater resilience.

Recreation of a hair follicle regenerative microenvironment: Successes and pitfalls.

The hair follicle (HF) is an exquisite skin appendage endowed with cyclical regenerative capacity; however, de novo follicle formation does not naturally occur. Consequently, patients suffering from extensive skin damage or hair loss are deprived of the HF critical physiological and/or aesthetic functions, severally compromising skin function and the individual's psychosocial well-being. Translation of regenerative strategies has been prevented by the loss of trichogenic capacity that relevant cell populations undergo in culture and by the lack of suitable human-based in vitro testing platforms. Here, we provide a comprehensive overview of the major difficulties associated with HF regeneration and the approaches used to overcome these drawbacks. We describe key cellular requirements and discuss the importance of the HF extracellular matrix and associated signaling for HF regeneration. Finally, we summarize the strategies proposed so far to bioengineer human HF or hair-bearing skin models and disclose future trends for the field.

WDR60-mediated dynein-2 loading into cilia powers retrograde IFT and transition zone crossing.

The dynein-2 motor complex drives retrograde intraflagellar transport (IFT), playing a pivotal role in the assembly and functions of cilia. However, the mechanisms that regulate dynein-2 motility remain poorly understood. Here, we identify the Caenorhabditis elegans WDR60 homologue, WDR-60, and dissect the roles of this intermediate chain using genome editing and live imaging of endogenous dynein-2/IFT components. We find that loss of WDR-60 impairs dynein-2 recruitment to cilia and its incorporation onto anterograde IFT trains, reducing retrograde motor availability at the ciliary tip. Consistent with this, we show that fewer dynein-2 motors power WDR-60-deficient retrograde IFT trains, which move at reduced velocities and fail to exit cilia, accumulating on the distal side of the transition zone. Remarkably, disrupting the transition zone's NPHP module almost fully restores ciliary exit of underpowered retrograde trains in wdr-60 mutants. This work establishes WDR-60 as a major contributor to IFT, and the NPHP module as a roadblock to dynein-2 passage through the transition zone.

Dermal papilla cells and melanocytes response to physiological oxygen levels depends on their interactions.

BACKGROUND: Human dermal papilla (DP) cells and melanocytes (hMel) are central players in hair growth and pigmentation, respectively. In hair follicles (HFs), oxygen (O2 ) levels average 5%, being coupled with the production of reactive oxygen species (ROS), necessary to promote hair growth. MATERIALS AND METHODS: DP cell and hMel proliferation and phenotype were studied under physiological (5%O2 , physoxia) or atmospheric (21%O2 , normoxia) oxygen levels. hMel-DP cells interactions were studied in indirect co-culture or by directly co-culturing hMel with DP spheroids, to test whether their interaction affected the response to physoxia. RESULTS: Physoxia decreased DP cell senescence and improved their secretome and phenotype, as well as hMel proliferation, migration, and tyrosinase activity. In indirect co-cultures, physoxia affected DP cells' alkaline phosphatase (ALP) activity but their signalling did not influence hMel proliferation or tyrosinase activity. Additionally, ROS production was higher than in monocultures but a direct correlation between ROS generation and ALP activity in DP cells was not observed. In the 3D aggregates, where hMel are organized around the DP, both hMel tyrosinase and DP cells ALP activities, their main functional indicators, plus ROS production were higher in physoxia than normoxia. CONCLUSIONS: Overall, we showed that the response to physoxia differs according to hMel-DP cells interactions and that the microenvironment recreated when in direct contact favours their functions, which can be relevant for hair regeneration purposes.