The Rac1 homolog CED-10 is a component of the MES-1/SRC-1 pathway for asymmetric division of the C. elegans EMS blastomere.

Asymmetric cell division is essential for the creation of cell types with different identities and functions. The EMS blastomere of the four-cell Caenorhabditis elegans embryo undergoes an asymmetric division in response to partially redundant signaling pathways. One pathway involves a Wnt signal emanating from the neighboring P2 cell, while the other pathway is defined by the receptor-like MES-1 protein localized at the EMS/P2 cell contact, and the cytoplasmic kinase SRC-1. In response to these pathways, the EMS nuclear-centrosome complex rotates so that the spindle forms on the anterior-posterior axis; after division, the daughter cell contacting P2 becomes the endodermal precursor cell. Here we identify the Rac1 homolog, CED-10, as a new component of the MES-1/SRC-1 pathway. Loss of CED-10 affects both spindle positioning and endoderm specification. Although MES-1 is still present at the EMS/P2 contact in ced-10 embryos, SRC-1 dependent phosphorylation is reduced. These and other results suggest that CED-10 acts downstream of MES-1 and upstream of, or at the level of, SRC-1 activity. In addition, we find that the branched actin regulator ARX-2 is enriched at the EMS/P2 cell contact site, in a CED-10 dependent manner. Loss of ARX-2 results in spindle positioning defects, suggesting that CED-10 acts through branched actin to promote the asymmetric division of the EMS cell.

Cannabis and Cannabinoids in Adults With Cancer: ASCO Guideline.

PURPOSE: To guide clinicians, adults with cancer, caregivers, researchers, and oncology institutions on the medical use of cannabis and cannabinoids, including synthetic cannabinoids and herbal cannabis derivatives; single, purified cannabinoids; combinations of cannabis ingredients; and full-spectrum cannabis. METHODS: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and cohort studies on the efficacy and safety of cannabis and cannabinoids when used by adults with cancer. Outcomes of interest included antineoplastic effects, cancer treatment toxicity, symptoms, and quality of life. PubMed and the Cochrane Library were searched from database inception to January 27, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: The evidence base consisted of 13 systematic reviews and five additional primary studies (four RCTs and one cohort study). The certainty of evidence for most outcomes was low or very low. RECOMMENDATIONS: Cannabis and/or cannabinoid access and use by adults with cancer has outpaced the science supporting their clinical use. This guideline provides strategies for open, nonjudgmental communication between clinicians and adults with cancer about the use of cannabis and/or cannabinoids. Clinicians should recommend against using cannabis or cannabinoids as a cancer-directed treatment unless within the context of a clinical trial. Cannabis and/or cannabinoids may improve refractory, chemotherapy-induced nausea and vomiting when added to guideline-concordant antiemetic regimens. Whether cannabis and/or cannabinoids can improve other supportive care outcomes remains uncertain. This guideline also highlights the critical need for more cannabis and/or cannabinoid research.Additional information is available at www.asco.org/supportive-care-guidelines.

Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy.

In humans, balanced invasion of trophoblast cells into the uterine mucosa, the decidua, is critical for successful pregnancy. Evidence suggests that this process is regulated by uterine natural killer (uNK) cells, but how they influence reproductive outcomes is unclear. Here, we used our trophoblast organoids and primary tissue samples to determine how uNK cells affect placentation. By locating potential interaction axes between trophoblast and uNK cells using single-cell transcriptomics and in vitro modeling of these interactions in organoids, we identify a uNK cell-derived cytokine signal that promotes trophoblast differentiation at the late stage of the invasive pathway. Moreover, it affects transcriptional programs involved in regulating blood flow, nutrients, and inflammatory and adaptive immune responses, as well as gene signatures associated with disorders of pregnancy such as pre-eclampsia. Our findings suggest mechanisms on how optimal immunological interactions between uNK cells and trophoblast enhance reproductive success.

The microstratigraphy and depositional environments of Lida Ajer and Ngalau Gupin, two fossil-bearing tropical limestone caves of west Sumatra.

Lida Ajer and Ngalau Gupin are karstic caves situated in the Padang Highlands, western Sumatra, Indonesia. Lida Ajer is best known for yielding fossil evidence that places the arrival of Homo sapiens in Southeast Asia during Marine Isotope Stage 4, one of the earliest records for the region. Ngalau Gupin recently produced the first record of hippopotamid Hexaprotodon on the island, representing the only globally extinct taxon in Pleistocene deposits from Sumatra. Microstratigraphic (micromorphological) analyses were applied to unconsolidated fossil-bearing cave sediments from these two sites. We use micromorphology as part of a micro-contextualised taphonomic approach to identify the diagenetic processes affecting fossils and sediments within these caves, through phases of their depositional history. The fossil-bearing sediments in Lida Ajer have been subjected to a suite of natural sedimentation processes ranging from water action to carnivore occupation, which would indicate the fossils underwent significant reworking prior to lithification of the deposit. The results demonstrate that the base of the unconsolidated fossil-bearing sediments in Ngalau Gupin were derived from the interior of the cave, where the matrix was partially phosphatized as a result of guano-driven diagenesis. These observations can be used to test hypotheses about the integrity of incorporated vertebrate remains and to aid in local palaeoenvironmental reconstructions. The methods employed in this research have not previously been applied to cave sediments from sites in the Padang Highlands and provide key new insights into the palaeontological and natural history of the western region of Sumatra.

An arginase 2 promoter transgenic line illuminates immune cell polarisation in zebrafish.

Innate immune responses to inflammation and infection are complex and represent major challenges for developing much needed new treatments for chronic inflammatory diseases and drug-resistant infections. To be ultimately successful, the immune response must be balanced to allow pathogen clearance without excess tissue damage, processes controlled by pro- and anti-inflammatory signals. The roles of anti-inflammatory signalling in raising an appropriate immune response are underappreciated, representing overlooked potential drug targets. This is especially true in neutrophils, a difficult cell type to study ex vivo owing to a short lifespan, dogmatically seen as being highly pro-inflammatory. Here, we have generated and describe the first zebrafish transgenic line [TgBAC(arg2:eGFP)sh571] that labels expression of the anti-inflammatory gene arginase 2 (arg2) and show that a subpopulation of neutrophils upregulate arginase soon after immune challenge with injury and infection. At wound-healing stages, arg2:GFP is expressed in subsets of neutrophils and macrophages, potentially representing anti-inflammatory, polarised immune cell populations. Our findings identify nuanced responses to immune challenge in vivo, responses that represent new opportunities for therapeutic interventions during inflammation and infection.

A new model for general practice-led, regional, community-based, memory clinics.

BACKGROUND: Dementia is a major international health issue with high impact on the patient, relatives, and broader society. Routine screening for dementia is limited, despite known benefit of early detection and intervention on quality of care and patient outcomes. Screening is particularly limited in rural and regional areas, despite high burden and projected growth of dementia in these populations. The current study aimed to implement a new general practitioner (GP) led, multidisciplinary, model of care providing dementia detection and referral pathway to a community-based specialist clinic across six regional general practices. METHODS: Cross-sectional analysis of dementia screening and referral characteristics in the St Anthony Family Medical Practices group based in the regional area of Loddon-Mallee, Victoria. Data were collected on demographics and relevant medical history. Cognitive state was assessed using the Mini-Mental State Examination (MMSE), GP Assessment of Cognition (GPCog), and Geriatric Depression Scale (GDS). Referrals and referral outcomes were recorded for geriatrician, psycho-geriatrician, or both. RESULTS: Eight hundred and eighteenth patients over 65 years were screened, accounting for approximately 24.2% of 65 and over presentations for the practice network. Of those screened, 68.9% were indicated for referral and 30.3% of these were successfully referred. Of the indicated patients who received referrals, 34.2% declined. Many who declined referral had intermediate scores on the cognitive assessments utilized. CONCLUSION: Standardised models of care, integrated within community services, are necessary to improve access to early detection, referral and quality management of dementia. The St Anthony Memory Service model will be invaluable in informing future service development, and in particular the development of services for people living with dementia in rural and regional communities.

Developing Faith-Based Health Promotion Programs that Target Cardiovascular Disease and Cancer Risk Factors.

The aim of this study was to evaluate the impact of a faith-based health promotion program on the ideal health behaviors shared between cardiovascular disease (CVD) and cancer. The primary purpose was to measure the individual-level change in three categories of shared risk behaviors between CVD and cancer (body weight, physical activity, and nutrition) among program participants. Additionally, we evaluated the association of churches' perceived environmental support on these ideal health behaviors. Baseline and 10-week surveys were conducted to assess BMI, ideal health behaviors (diet and physical activity), and a Healthy Lifestyle Score (HLS) was created to measure adherence to health behaviors. A Supportive Church Environment Score (SCES) was designed to address the second objective. Psychosocial factors (stress and coping skills) and demographics were also measured. The percentage of participants meeting diet and exercise recommendations significantly increased with the completion of the program. Whole-grain intake increased by 64% (p = 0.085), vegetable intake increased by 58% (p = < 0.001), fruit intake increased by 39% (p = < 0.001), physical activity increased by 14% (p = < 0.001), and red meat consumption decreased by 19% (p = < 0.001). The median HLS increased from 7 to 8 (p = < 0.001). At baseline the association between ideal health behaviors and the SCES was significant for fruit intake (r = 0.22, p-value = 0.003) and red meat consumption (r = 0.17, p-value = 0.02). The aggregate behaviors as represented by the HLS were associated with the SCES (r = 0.19, p-value = 0.03). The significant increase in the HLS indicates an average improvement in the degree to which participants were meeting recommendations after completing the program. Therefore, adherence to these ideal health behaviors increased over the 10-week program.

Patients and Partners in Research: Patient and Caregiver Perceptions of Research Engagement and the Role of Their Psychosocial States in Participation.

Multiple sclerosis (MS) is one of the most common, nontraumatic, disabling diseases diagnosed in adults. Self-empowered patients and families are valued members of the MS research team. The objective of this study was to explore patient and family perceptions of the influence of psychosocial state on their willingness to be research partners. Researchers conducted 5 focus groups with MS patients and family from the Upper Midwest Chapter of the National Multiple Sclerosis Society. The researchers asked questions addressing psychosocial factors influencing ability and willingness to work with MS researchers as partners. Relevant themes were identified including comfort level of individuals in formulating research questions, comfort level engaging in research, understanding of the meaning of research and self-perception about skills, research training, and knowledge needs. The findings of this study support the role of MS patients' perspectives about MS, their understanding of the science of MS, and role of their psychosocial states as all these factors were patient identified as being key to their ability to be active, engaged and willing research participants.

Functional Characterization of Rare Genetic Variants in the N-Terminus of Complement Factor H in aHUS, C3G, and AMD.

Membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD) have all been strongly linked with dysfunction of the alternative pathway (AP) of complement. A significant proportion of individuals with MPGN, C3G, aHUS and AMD carry rare genetic variants in the CFH gene that cause functional or quantitative deficiencies in the factor H (FH) protein, an important regulator of the AP. In silico analysis of the deleteriousness of rare genetic variants in CFH is not reliable and careful biochemical assessment remains the gold standard. Six N-terminal variants of uncertain significance in CFH were identified in patients with these diseases of the AP and selected for analysis. The variants were produced in Pichia Pastoris in the setting of FH CCPs 1-4, purified by nickel affinity chromatography and size exclusion and characterized by surface plasmon resonance and haemolytic assays as well as by cofactor assays in the fluid phase. A single variant, Q81P demonstrated a profound loss of binding to C3b with consequent loss of cofactor and decay accelerating activity. A further 2 variants, G69E and D130N, demonstrated only subtle defects which could conceivably over time lead to disease progression of more chronic AP diseases such as C3G and AMD. In the variants S159N, A161S, and M162V any functional defect was below the capacity of the experimental assays to reliably detect. This study further underlines the importance of careful biochemical assessment when assigning functional consequences to rare genetic variants that may alter clinical decisions for patients.

Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline.

PURPOSE: To provide guidance regarding best practices in the prevention and management of medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer. METHODS: Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. Guideline development involved a systematic review of the literature and a formal consensus process. PubMed and EMBASE were searched for studies of the prevention and management of MRONJ related to bone-modifying agents (BMAs) for oncologic indications published between January 2009 and December 2017. Results from an earlier systematic review (2003 to 2008) were also included. RESULTS: The systematic review identified 132 publications, only 10 of which were randomized controlled trials. Recommendations underwent two rounds of consensus voting. RECOMMENDATIONS: Currently, MRONJ is defined by (1) current or previous treatment with a BMA or angiogenic inhibitor, (2) exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region and that has persisted for longer than 8 weeks, and (3) no history of radiation therapy to the jaws or metastatic disease to the jaws. In patients who initiate a BMA, preventive care includes comprehensive dental assessments, discussion of modifiable risk factors, and avoidance of elective dentoalveolar surgery (ie, surgery that involves the teeth or contiguous alveolar bone) during BMA treatment. It remains uncertain whether BMAs should be discontinued before dentoalveolar surgery. Staging of MRONJ should be performed by a clinician with experience in the management of MRONJ. Conservative measures comprise the initial approach to MRONJ treatment. Ongoing collaboration among the dentist, dental specialist, and oncologist is essential to optimal patient care.

Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update.

PURPOSE: To update the ASCO clinical practice guideline on adjuvant endocrine therapy based on emerging data about the optimal duration of aromatase inhibitor (AI) treatment. METHODS: ASCO conducted a systematic review of randomized clinical trials from 2012 to 2018. Guideline recommendations were based on the Panel's review of the evidence from six trials. RESULTS: The six included studies of AI treatment beyond 5 years of therapy demonstrated that extension of AI treatment was not associated with an overall survival advantage but was significantly associated with lower risks of breast cancer recurrence and contralateral breast cancer compared with placebo. Bone-related toxic effects were more common with extended AI treatment. RECOMMENDATIONS: The Panel recommends that women with node-positive breast cancer receive extended therapy, including an AI, for up to a total of 10 years of adjuvant endocrine treatment. Many women with node-negative breast cancer should consider extended therapy for up to a total of 10 years of adjuvant endocrine treatment based on considerations of recurrence risk using established prognostic factors. The Panel noted that the benefits in absolute risk of reduction were modest and that, for lower-risk node-negative or limited node-positive cancers, an individualized approach to treatment duration that is based on considerations of risk reduction and tolerability was appropriate. A substantial portion of the benefit for extended adjuvant AI therapy was derived from prevention of second breast cancers. Shared decision making between clinicians and patients is appropriate for decisions about extended adjuvant endocrine treatment, including discussions about the absolute benefits in the reduction of breast cancer recurrence, the prevention of second breast cancers, and the impact of adverse effects of treatment. Additional information can be found at www.asco.org/breast-cancer-guidelines .

5 drug interactions you don't want to miss.

These interactions can affect contraceptive efficacy, increase bleeding risk, or lead to rhabdomyolysis. This practical guide can help you avoid trouble.

Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression.

PURPOSE: To update the ASCO adjuvant endocrine therapy guideline based on emerging data concerning the benefits and risks of ovarian suppression in addition to standard adjuvant therapy in premenopausal women with estrogen receptor-positive breast cancer. METHODS: ASCO convened an Update Panel and conducted a systematic review of randomized clinical trials investigating ovarian suppression. RESULTS: Two trials investigating the addition of ovarian suppression to tamoxifen did not show an overall clinical benefit for ovarian suppression. Nonetheless, the addition of ovarian suppression to standard adjuvant therapy with tamoxifen or with an aromatase inhibitor improved disease-free survival and improved freedom from breast cancer and distant recurrence compared with tamoxifen alone among the subset of patients who were at sufficient risk for recurrence such that adjuvant chemotherapy was warranted. Compared with tamoxifen alone, ovarian suppression was associated with a substantial increase in menopausal symptoms, sexual dysfunction, and diminished quality of life. RECOMMENDATIONS: The Panel recommends that higher-risk patients should receive ovarian suppression in addition to adjuvant endocrine therapy, whereas lower-risk patients should not. Women with stage II or III breast cancers who would ordinarily be advised to receive adjuvant chemotherapy should receive ovarian suppression with endocrine therapy. The panel recommends that some women with stage I or II breast cancers at higher risk of recurrence who might consider chemotherapy may also be offered ovarian suppression with endocrine therapy. Women with stage I breast cancers not warranting chemotherapy should not receive ovarian suppression, nor should women with node-negative cancers 1 cm or less. Ovarian suppression may be administered with either tamoxifen or an aromatase inhibitor. Additional information is available at www.asco.org/guidelines/endocrinebreast and www.asco.org/guidelineswiki.

A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H-Related 3 Gene in Atypical Hemolytic Uremic Syndrome.

The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.

Preventable Infections in Children with Leukodystrophy.

Children with inherited leukodystrophies have high hospitalization rates, often associated with infection. We studied whether potentially modifiable risk factors (pre-existing in-dwelling central intravenous access, urinary catheter, hardware, or mechanical ventilation; and influenza vaccine) were associated with infection-related hospitalization in children with leukodystrophy. Central intravenous access was associated with sepsis (odds ratio (OR) 9.8); urinary catheter was associated with urinary tract infections (OR 9.0); lack of seasonal vaccination was associated with influenza (OR 6.4); and mechanical ventilation was associated with pneumonia (OR 2.7). We conclude that potentially modifiable risk factors are significantly associated with infection and hospitalization in children with leukodystrophies.

Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update.

PURPOSE: To update the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment, particularly adjuvant tamoxifen. METHODS: ASCO convened the Update Committee and conducted a systematic review of randomized clinical trials from January 2009 to June 2013 and analyzed three historical trials. Guideline recommendations were based on the Update Committee's review of the evidence. Outcomes of interest included survival, disease recurrence, and adverse events. RESULTS: This guideline update reflects emerging data on duration of tamoxifen treatment. There have been five studies of tamoxifen treatment beyond 5 years of therapy. The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year durations of tamoxifen use. In addition to modest gains in survival, extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer. RECOMMENDATIONS: Previous ASCO guidelines recommended treatment of women who have hormone receptor-positive breast cancer and are premenopausal with 5 years of tamoxifen, and those who are postmenopausal a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor (in sequence). If women are pre- or perimenopausal and have received 5 years of adjuvant tamoxifen, they should be offered 10 years total duration of tamoxifen. If women are postmenopausal and have received 5 years of adjuvant tamoxifen, they should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy.

Characterization of a factor H mutation that perturbs the alternative pathway of complement in a family with membranoproliferative GN.

Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.