Roadmap for the Emerging Field of Cancer Neuroscience.

Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of "cancer neuroscience" and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.

Exocrine gland structure-function relationships.

Fluid secretion by exocrine glandular organs is essential to the survival of mammals. Each glandular unit within the body is uniquely organized to carry out its own specific functions, with failure to establish these specialized structures resulting in impaired organ function. Here, we review glandular organs in terms of shared and divergent architecture. We first describe the structural organization of the diverse glandular secretory units (the end-pieces) and their fluid transporting systems (the ducts) within the mammalian system, focusing on how tissue architecture corresponds to functional output. We then highlight how defects in development of end-piece and ductal architecture impacts secretory function. Finally, we discuss how knowledge of exocrine gland structure-function relationships can be applied to the development of new diagnostics, regenerative approaches and tissue regeneration.

Client perspectives on psychotherapy failure.

This study qualitatively examined client's definition and experiences of failed psychotherapy.Thirteen clients were interviewed by phone regarding their experience of failed psychotherapy. Data were analyzed using consensual qualitative research (CQR).Participants defined failed psychotherapy as negatively affecting clients, involving problems in the psychotherapy relationship, and not meeting clients' goals. When describing specific experiences of failed psychotherapy, participants gradually recognized the failure themselves, but the recognition was sometimes facilitated by others. Pre-termination, the failed psychotherapy yielded negative effects (worsened symptoms/functioning, deteriorating relationship, not addressing clients' concerns). Participants perceived therapists' contributions as involving action (insensitive/inappropriate responses to participants' concerns about psychotherapy) and inaction (not managing psychotherapy effectively). They perceived their own contributions as their difficulty voicing their concerns or asserting themselves. Post-termination effects were negative cognitively/affectively (heightened distress), behaviorally (disinterest in seeking mental health services), and interpersonally (relationship difficulties in later psychotherapy); the failed psychotherapy also helped participants pursue their needs in psychotherapy.Failed psychotherapy consisted of problems in the relationship and the treatment not meeting client's goals. Such psychotherapy worsened clients' functioning, further damaged an already tenuous psychotherapy relationship, and both therapists and clients contributed to the failure. After termination, failed psychotherapy yielded cognitive/affective, behavioral, and interpersonal effects.

Patient perspectives on working with preferences in psychotherapy: A consensual qualitative research study.

OBJECTIVE: Assessing and accommodating patient preferences is integral to evidence-based practice. This qualitative study sought to explore patient perspectives and experiences of preference work in psychotherapy. METHODS: Participants were 13 UK-based patients who had completed up to 24 sessions of a collaborative-integrative psychotherapy. Ten participants identified as female and three as male. Interviews were conducted at endpoint and analyzed using a team-based, consensual qualitative research approach. RESULTS: Three superordinate domains were developed: Preferences Themselves, Process of Working with Preferences in Psychotherapy, and Effect of Preference Work (or its Absence). Patients typically wanted leadership, challenge, and input from their psychotherapist, and an affirming style. Patients attributed the origin of their preferences to personal history, characteristics, or circumstances; the present psychotherapy; or past episodes of psychotherapy. Some preferences changed over time. Preference work was described as having positive effects on the therapeutic relationship and patients' intrapersonal worlds; however, variantly, non-accommodation of preferences was also experienced as beneficial. CONCLUSION: Our findings provide in-depth answers to a range of novel questions on preference work-potential mechanisms by which preference work impacts outcomes, factors that may facilitate preference work, and origins of preferences-as well as nuancing previously-established quantitative findings. Implications for clinical training and practice are discussed.

Diverse progenitor cells preserve salivary gland ductal architecture after radiation-induced damage.

The ductal system of the salivary gland has long been postulated to be resistant to radiation-induced damage, a common side effect incurred by head and neck cancer patients receiving radiotherapy. Yet, whether the ducts are capable of regenerating after genotoxic injury, or whether damage to ductal cells induces lineage plasticity, as has been reported in other organ systems, remains unknown. Here, using the murine salivary gland, we show that two ductal progenitor populations, marked exclusively by KRT14 and KIT, maintain non-overlapping ductal compartments after radiation exposure but do so through distinct cellular mechanisms. KRT14+ progenitor cells are fast-cycling cells that proliferate in response to radiation-induced damage in a sustained manner and divide asymmetrically to produce differentiated cells of the larger granulated ducts. Conversely, KIT+ intercalated duct cells are long-lived progenitors for the intercalated ducts that undergo few cell divisions either during homeostasis or after gamma radiation, thus maintaining ductal architecture with slow rates of cell turnover. Together, these data illustrate the regenerative capacity of the salivary ducts and highlight the heterogeneity in the damage responses used by salivary progenitor cells to maintain tissue architecture.

Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes.

Xerostomia (dry mouth) is the most common side effect of radiation therapy in patients with head and neck cancer and causes difficulty speaking and swallowing. Since aldehyde dehydrogenase 3A1 (ALDH3A1) is highly expressed in mouse salivary stem/progenitor cells (SSPCs), we sought to determine the role of ALDH3A1 in SSPCs using genetic loss-of-function and pharmacologic gain-of-function studies. Using DarkZone dye to measure intracellular aldehydes, we observed higher aldehyde accumulation in irradiated Aldh3a1-/- adult murine salisphere cells and in situ in whole murine embryonic salivary glands enriched in SSPCs compared with wild-type glands. To identify a safe ALDH3A1 activator for potential clinical testing, we screened a traditional Chinese medicine library and isolated d-limonene, commonly used as a food-flavoring agent, as a single constituent activator. ALDH3A1 activation by d-limonene significantly reduced aldehyde accumulation in SSPCs and whole embryonic glands, increased sphere-forming ability, decreased apoptosis, and improved submandibular gland structure and function in vivo after radiation. A phase 0 study in patients with salivary gland tumors showed effective delivery of d-limonene into human salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for mitigating xerostomia in patients with head and neck cancer receiving radiation therapy.

Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland.

The tear-producing lacrimal gland is a tubular organ that protects and lubricates the ocular surface. The lacrimal gland possesses many features that make it an excellent model in which to investigate tubulogenesis, but the cell types and lineage relationships that drive lacrimal gland formation are unclear. Using single-cell sequencing and other molecular tools, we reveal novel cell identities and epithelial lineage dynamics that underlie lacrimal gland development. We show that the lacrimal gland from its earliest developmental stages is composed of multiple subpopulations of immune, epithelial and mesenchymal cell lineages. The epithelial lineage exhibits the most substantial cellular changes, transitioning through a series of unique transcriptional states to become terminally differentiated acinar, ductal and myoepithelial cells. Furthermore, lineage tracing in postnatal and adult glands provides the first direct evidence of unipotent KRT5+ epithelial cells in the lacrimal gland. Finally, we show conservation of developmental markers between the developing mouse and human lacrimal gland, supporting the use of mice to understand human development. Together, our data reveal crucial features of lacrimal gland development that have broad implications for understanding epithelial organogenesis.

Alterations in corneal biomechanics underlie early stages of autoimmune-mediated dry eye disease.

Autoimmune-mediated dry eye disease is a pathological feature of multiple disorders including Sjögren's syndrome, lupus and rheumatoid arthritis that has a life-long, detrimental impact on vision and overall quality of life. Although late stage disease outcomes such as epithelial barrier dysfunction, reduced corneal innervation and chronic inflammation have been well characterized in both human patients and mouse models, there is little to no understanding of early pathological processes. Moreover, the mechanisms underlying the loss of cornea homeostasis and disease progression are unknown. Here, we utilize the autoimmune regulatory (Aire)-deficient mouse model of autoimmune-mediated dry eye disease in combination with genome wide transcriptomics, high-resolution imaging and atomic force microscopy to reveal a potential extracellular matrix (ECM)-biomechanical-based mechanism driving cellular and morphological changes at early disease onset. Early disease in the Aire-deficient mouse model is associated with a mild reduction in tear production and moderate immune cell infiltration, allowing for interrogation of cellular, molecular and biomechanical changes largely independent of chronic inflammation. Using these tools, we demonstrate for the first time that the emergence of autoimmune-mediated dry eye disease is associated with an alteration in the biomechanical properties of the cornea. We reveal a dramatic disruption of the synthesis and organization of the extracellular matrix as well as degradation of the epithelial basement membrane during early disease. Notably, we provide evidence that the nerve supply to the cornea is severely reduced at early disease stages and that this is independent of basement membrane destruction or significant immune cell infiltration. Furthermore, diseased corneas display spatial heterogeneity in mechanical, structural and compositional changes, with the limbal compartment often exhibiting the opposite response compared to the central cornea. Despite these differences, however, epithelial hyperplasia is apparent in both compartments, possibly driven by increased activation of IL-1R1 and YAP signaling pathways. Thus, we reveal novel perturbations in corneal biomechanics, matrix organization and cell behavior during the early phase of dry eye that may underlie disease development and progression, presenting new potential targets for therapeutic intervention.

The emerging role of cranial nerves in shaping craniofacial development.

Organs and structures of the vertebrate head perform a plethora of tasks including visualization, digestion, vocalization/communication, auditory functions, and respiration in response to neuronal input. This input is primarily derived from afferent and efferent fibers of the cranial nerves (sensory and motor respectively) and efferent fibers of the cervical sympathetic trunk. Despite their essential contribution to the function and integration of processes necessary for survival, how organ innervation is established remains poorly understood. Furthermore, while it has been appreciated for some time that innervation of organs by cranial nerves is regulated in part by secreted factors and cell surface ligands expressed by those organs, whether nerves also regulate the development of facial organs is only beginning to be elucidated. This review will provide an overview of cranial nerve development in relation to the organs they innervate, and outline their known contributions to craniofacial development, thereby providing insight into how nerves may shape the organs they innervate during development. Throughout, the interaction between different cell and tissue types will be highlighted.

Salivary gland stem cells: A review of development, regeneration and cancer.

Salivary glands are responsible for maintaining the health of the oral cavity and are routinely damaged by therapeutic radiation for head and neck cancer as well as by autoimmune diseases such as Sjögren's syndrome. Regenerative approaches based on the reactivation of endogenous stem cells or the transplant of exogenous stem cells hold substantial promise in restoring the structure and function of these organs to improve patient quality of life. However, these approaches have been hampered by a lack of knowledge on the identity of salivary stem cell populations and their regulators. In this review we discuss our current knowledge on salivary stem cells and their regulators during organ development, homeostasis and regeneration. As increasing evidence in other systems suggests that progenitor cells may be a source of cancer, we also review whether these same salivary stem cells may also be cancer initiating cells.

miR-205 is a critical regulator of lacrimal gland development.

The tear film protects the terrestrial animal's ocular surface and the lacrimal gland provides important aqueous secretions necessary for its maintenance. Despite the importance of the lacrimal gland in ocular health, molecular aspects of its development remain poorly understood. We have identified a noncoding RNA (miR-205) as an important gene for lacrimal gland development. Mice lacking miR-205 fail to properly develop lacrimal glands, establishing this noncoding RNA as a key regulator of lacrimal gland development. Specifically, more than half of knockout lacrimal glands never initiated, suggesting a critical role of miR-205 at the earliest stages of lacrimal gland development. RNA-seq analysis uncovered several up-regulated miR-205 targets that may interfere with signaling to impair lacrimal gland initiation. Supporting this data, combinatorial epistatic deletion of Fgf10, the driver of lacrimal gland initiation, and miR-205 in mice exacerbates the lacrimal gland phenotype. We develop a molecular rheostat model where miR-205 modulates signaling pathways related to Fgf10 in order to regulate glandular development. These data show that a single microRNA is a key regulator for early lacrimal gland development in mice and highlights the important role of microRNAs during organogenesis.

Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren's Syndrome.

Sjögren's syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify tissue programs associated with disease onset using transcriptomic and immunohistological analysis of LGs from 5- and 7-week-old mice deficient in autoimmune response element (Aire). At 5 weeks of age (wk), Aire-/- mice show minimal tissue dysfunction and destruction compared to 7 wk Aire-/-, which exhibit severe dry eye, poor tear secretion, extensive lymphocytic infiltration, reduced functional innervation, and increased vascularization. Despite this mild phenotype, 5 wk Aire-/- LGs were highly enriched for signaling pathways previously associated with SS, including interferon gamma (IFNγ), interleukin 1 beta (IL1ß), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR) signaling, and interleukin-6/signal transducer and activator of transcription 3 (IL6/STAT3) signaling. Novel signaling pathways such as the semaphorin⁻plexin pathway were also noted. Intriguingly, we found an expansion of the ductal network with increasing disease. Activated STAT3, a blocker of apoptosis, was restricted to the ductal system and also increased with damage, highlighting its potential as a promoter of ductal cell survival. These data demonstrate the early activation of signaling pathways regulating inflammation, innervation, and cell survival before the onset of clinical disease indicators, suggesting their potential value as diagnostic biomarkers.

Meaning in life in psychotherapy: The perspective of experienced psychotherapists.

OBJECTIVE: Our goal was to explore the meaning experienced psychotherapists derive from providing psychotherapy, their beliefs about the role of meaning in life (MIL) in psychotherapy, how they worked with MIL with a client who explicitly presented concerns about MIL, and how they worked with a different client for whom MIL was a secondary and more implicit concern. METHOD: Thirteen experienced psychotherapists were interviewed and data were analyzed using consensual qualitative research. RESULTS: Therapists derived self-oriented meaning (e.g., feeling gratified, fulfilled, connected) and other-oriented meaning (helping others, making the world a better place) from providing psychotherapy. They believed that MIL is fundamental and underlies all human concerns, including those brought to therapy. In contrast to the clients who had implicit MIL concerns, clients who explicitly presented MIL concerns were reported to have more interpersonal problems and physical problems, but about the same amount of psychological distress and loss/grief. Therapists used insight-oriented interventions, support, action-oriented interventions, and exploratory interventions to work with MIL with both types of clients, but used more exploratory interventions with implicit than explicit MIL clients. CONCLUSIONS: MIL is a salient topic for experienced, existentially oriented psychotherapists; they work with MIL extensively with some clients in psychotherapy. We recommend that therapists receive training to work with MIL in therapy, and that they pay attention to MIL concerns when they conduct psychotherapy. We also recommend additional research on MIL in psychotherapy.

Dreaming of you: client and therapist dreams about each other during psychodynamic psychotherapy.

OBJECTIVES: Our objectives were to describe the frequency of therapists' dreams about their clients and clients' dreams about their therapists, to determine how therapists and clients who had such dreams differed from those who did not have such dreams, whether therapy process and outcome differed for those who had and did not have such dreams, and to describe the content and consequences of these dreams. METHODS: Thirteen doctoral student therapists conducted psychodynamic psychotherapy with 63 clients in a community clinic. RESULTS: Therapists who had dreams about clients had higher estimated and actual dream recall than did therapists who did not dream about clients. Qualitative analyses indicated that therapists' dreams yielded insights about the therapist, clients, and therapy; therapists used insights in their work with the clients. Among the clients, only two (who were particularly high in attachment anxiety and who feared abandonment from their therapists) reported dreams that were manifestly about their therapists. CONCLUSIONS: Therapists-in-training dreamed more about their clients than their clients dreamed about them. Dreams about clients can be used by therapists to understand themselves, clients, and the dynamics of the therapy relationship.

Depressive symptom clusters and 5-year incidence of coronary artery calcification: the coronary artery risk development in young adults study.

BACKGROUND: Because depression is a multidimensional construct and few studies have compared the relative importance of its facets in predicting cardiovascular risk, we evaluated the utility of depressive symptom clusters in predicting the 5-year incidence of coronary artery calcification (CAC). METHODS AND RESULTS: Participants were 2171 middle-aged adults (58% female; 43% black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who were free of cardiovascular disease. Depressive symptom clusters (z scores) were measured by questionnaires in 2000 to 2001, and CAC was measured by electron beam computed tomography in 2000 to 2001 and 2005 to 2006. There were 243 cases (11%) of incident CAC, defined as the absence of CAC at baseline and the presence of CAC at follow-up. Total depressive symptoms (odds ratio, 1.16; 95% confidence interval, 1.02-1.33; P=0.03) and the depressed affect cluster (odds ratio, 1.17; 95% confidence interval, 1.03-1.33; P=0.02) predicted incident CAC; however, the somatic, interpersonal distress, low positive affect, and pessimism clusters did not. The depressed affect-incident CAC relationship was independent of age, sex, race, education, and antidepressant use; was similar across sex and racial groups; and was partially accounted for by tobacco use and mean arterial pressure. CONCLUSIONS: In contrast to recent results indicating that the somatic cluster is the most predictive of cardiovascular outcomes, we found that the prospective association between depressive symptoms and incident CAC was driven by the depressed affect cluster. Our findings raise the possibility that there may not be 1 facet of depression that is the most cardiotoxic across all contexts.

Circulating maternal perfluoroalkyl substances during pregnancy in the C8 Health Study.

Perfluoroalkyl substances are manmade chemicals used in many consumer products and have become ubiquitous in the environment. Animal studies and a limited number of human studies have demonstrated developmental effects in offspring exposed to perfluoroalkyl substances in utero, but the implications of timing of in utero exposure have not been systematically investigated. The present study investigated variation in perfluorocarbon levels of 9952 women of childbearing age who had been exposed to perfluorooctanoic acid (PFOA) in drinking water contaminated by industrial waste. An analysis of variance with contrast was performed to compare the levels of PFOA and perfluorooctanesulfonic acid (PFOS) in pregnant and nonpregnant women overall and during each trimester of pregnancy. We found that pregnant women had lower circulating PFOA and PFOS concentrations in peripheral blood than nonpregnant women and that PFOA levels were consistently lower throughout all trimesters for pregnancy, suggesting transfer to the fetus at an early stage of gestation. These results are discussed in the context of the endocrine-disrupting properties of perfluoroalkyl substances that have been characterized in animal and human studies. Our conclusion is that further, systematic study of the potential implications of intrauterine perfluorocarbon exposure during critical periods of fetal development is urgently needed.

Psychotherapist advice, suggestions, recommendations: A research review.

Psychotherapists provide at least some advice, suggestions, and recommendations (ASR) in most treatment approaches. We define ASR, offer clinical examples, and review the research evidence for the immediate in-session, immediate delayed, and intermediate effects of ASR, as well as for the moderators of these effects in individual psychotherapy. In seven studies with 327 clients and 131 therapists, we found evidence of neutral immediate in-session outcomes (e.g., client experiencing levels), neutral immediate delayed outcomes (e.g., client-rated helpfulness during postsession videotape reviews), and positive intermediate outcomes (e.g., implementation of recommendations as rated in subsequent sessions) for ASR. These differences may be related to methodological variations in studies in addition to the different timing of the outcome measurement. In terms of moderators, there is some evidence that the working alliance, client collaboration prior to the ASR, content of the ASR, and therapist and client attachment styles moderate the effects of immediate in-session outcomes, and that type, difficulty, and therapist influence moderate the effects of intermediate outcomes of ASR. We conclude with research limitations, training implications, and therapeutic practices related to ASR. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The First Transcriptomic Atlas of the Adult Lacrimal Gland Reveals Epithelial Complexity and Identifies Novel Progenitor Cells in Mice.

The lacrimal gland (LG) secretes aqueous tears. Previous studies have provided insights into the cell lineage relationships during tissue morphogenesis. However, little is known about the cell types composing the adult LG and their progenitors. Using scRNAseq, we established the first comprehensive cell atlas of the adult mouse LG to investigate the cell hierarchy, its secretory repertoire, and the sex differences. Our analysis uncovered the complexity of the stromal landscape. Epithelium subclustering revealed myoepithelial cells, acinar subsets, and two novel acinar subpopulations: Tfrchi and Car6hi cells. The ductal compartment contained Wfdc2+ multilayered ducts and an Ltf+ cluster formed by luminal and intercalated duct cells. Kit+ progenitors were identified as: Krt14+ basal ductal cells, Aldh1a1+ cells of Ltf+ ducts, and Sox10+ cells of the Car6hi acinar and Ltf+ epithelial clusters. Lineage tracing experiments revealed that the Sox10+ adult populations contribute to the myoepithelial, acinar, and ductal lineages. Using scRNAseq data, we found that the postnatally developing LG epithelium harbored key features of putative adult progenitors. Finally, we showed that acinar cells produce most of the sex-biased lipocalins and secretoglobins detected in mouse tears. Our study provides a wealth of new data on LG maintenance and identifies the cellular origin of sex-biased tear components.

A mechanism of gene evolution generating mucin function.

How novel gene functions evolve is a fundamental question in biology. Mucin proteins, a functionally but not evolutionarily defined group of proteins, allow the study of convergent evolution of gene function. By analyzing the genomic variation of mucins across a wide range of mammalian genomes, we propose that exonic repeats and their copy number variation contribute substantially to the de novo evolution of new gene functions. By integrating bioinformatic, phylogenetic, proteomic, and immunohistochemical approaches, we identified 15 undescribed instances of evolutionary convergence, where novel mucins originated by gaining densely O-glycosylated exonic repeat domains. Our results suggest that secreted proteins rich in proline are natural precursors for acquiring mucin function. Our findings have broad implications for understanding the role of exonic repeats in the parallel evolution of new gene functions, especially those involving protein glycosylation.

A synthetic tear protein resolves dry eye through promoting corneal nerve regeneration.

Corneal architecture is essential for vision and is greatly perturbed by the absence of tears due to the highly prevalent disorder dry eye. With no regenerative therapies available, pathological alterations of the ocular surface in response to dryness, including persistent epithelial defects and poor wound healing, result in lifelong morbidity. Here, using a mouse model of aqueous-deficient dry eye, we reveal that topical application of the synthetic tear protein Lacripep reverses the pathological outcomes of dry eye through restoring the extensive network of corneal nerves that are essential for tear secretion, barrier function, epithelial homeostasis, and wound healing. Intriguingly, the restorative effects of Lacripep occur despite extensive immune cell infiltration, suggesting tissue reinnervation and regeneration can be achieved under chronic inflammatory conditions. In summary, our data highlight Lacripep as a first-in-class regenerative therapy for returning the cornea to a near homeostatic state in individuals who suffer from dry eye.