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Background: Natural killer (NK) cells are important contributors to antitumor immunity in clear-cell renal cell carcinoma (ccRCC). However, their phenotype, function, and association with clinical outcomes in ccRCC remain poorly understood., Materials and Methods: We analyzed single-cell RNA sequencing data from 13 primary tumors, 1 localized tumor extension, and 1 metastasis from ccRCC patients at different clinical stages. For each primary tumor specimen, paired normal kidneys were also analyzed. Differential gene expression analysis was carried out to investigate NK cell phenotypes and to derive a gene expression signature. Gene signatures from NK cell subclusters of interest were used to interrogate bulk transcriptomic datasets and expression with clinical outcomes. Finally, tumor-infiltrating NK cell function (cytokine production and cytotoxicity) was assessed by isolation of live NK cells from ccRCC tissue, co-culture with K562 target cells, and measurement of cytokine production (interferon-γ) and cytotoxicity (CD107a) markers by flow cytometry., Results: Single-cell transcriptomic data were analyzed from 13 patients with ccRCC (tumor/normal kidney), resulting in 21 139 NK cells. Clustering analysis revealed six NK cell subsets. Bright-like NK cells were significantly enriched in advanced ccRCC compared with localized ccRCC and normal kidney, expressed markers of tissue residency (ZNF683/Hobit, ITGA1/CD49a, CD9, ITGAE/CD103), and had decreased expression of cytotoxicity genes (GZMB/Granzyme-B, PRF1/perforin). In independent cohorts (The Cancer Genome Atlas ccRCC cohort, CheckMate 025), a gene expression score representing this dysfunctional NK cell phenotype was enriched in advanced ccRCC and was associated with worse overall survival. Functional interrogation of tumor-infiltrating NK cells from ccRCC confirmed that tumor-resident CD49a+CD9+ NK cells had impaired cytotoxicity compared with CD49a-CD9- NK cells., Conclusions: A dysfunctional, tumor-resident NK cell phenotype was enriched among patients with metastatic disease and associated with worse survival in patients with advanced ccRCC across multiple patient cohorts. Restoration of NK cell function (via cytokine stimulation or NK cell engineering) could provide a novel avenue for therapeutic intervention against ccRCC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018)., Patients and Methods: Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints., Results: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months., Conclusions: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted., Competing Interests: Disclosure BAM reports consulting fees from BMS, Eisai, Exelixis, Gilead, Pfizer, SeaGen and research funding to institution from BMS, Exelixis, Pfizer, SeaGen. GPS reports consulting fees from, Genentech, EMD Serono, Merck, Astrazeneca, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma, PrecisCa, Primum. He serves on scientific advisory board for Suba Therapeutics, Syapse, Servier, Merck, Syncorp and reports research support to institution from Sanofi, Astrazeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, Jazz Therapeutics. He is a paid speaker for BIO – INFORMAÇÃO BRASILEIRA DE ONCOLOGIA Ltda, OLE Forum (Mexico), Seagen, Gilead, Natera, Exelixis, Janssen, Bayer, Aveo and serves on data safety monitoring committee honorarium for Mereo. His spouse is employed by Myriad. XG reports consulting fees from Bayer, Flare Therapeutics, Myovant, PathAI, PureTech Bio, Silverback Therapeutics. CMM reports consulting fees from Aadi Bioscience, Synthekine and research funding to institution from BMS. XXW reports consulting fees from Novartis and research funding to institution from BMS. JEB reports speaker honoraria from Guardant Health with consulting fees from Guardant Health, Genome Medical, Oncotect, Precede, TracerDx, Musculo, JucaBio. He has equity in Cityblock Health, Genome Medical, Oncotect, Precede, TracerDx, Musculo and institutional patent filed on methods to detect neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis. SAB reports consulting fees from BMS, Eisai, Exelixis, Seagen. PKR reports research funding to institution from Bayer, Telix, and Lilly. MDM reports scientific advisory boards for Merck and Janssen. TKC reports consulting fees from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO and others), outside the submitted work. He has institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA and equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium. He is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda, Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at DFCI. JB reports personal and institutional financial interests with Genentech, Pfizer, Bristol-Myers Squibb, AstraZeneca, Merck, Takeda, Eisai, Scholar Rock, Surface Oncology, Gilead, Ipsen, and Pierre-Fabre, trial sponsorship through Associació per a la Recerca Oncológia (APRO), royalties from UpToDate, stocks from Rainier Therapeutics, and a nonfinancial interest as President of APRO. All other authors have declared no conflicts of interest., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Purpose: To compare healthcare resource utilization (HRU) and costs associated with dose-dense methotrexate, vinblastine, doxorubicin, cisplatin (ddMVAC) and gemcitabine, cisplatin (GC) as neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC)., Methods: Patient treated at Dana-Farber Cancer Institute from 2010 to 2019 were identified. HRU data on chemotherapy administered, supportive medications, patient monitoring, clinic, infusion, emergency department (ED) visits and hospitalization were collected retrospectively. Unit costs for HRU components were obtained from the Centers for Medicare and Medicaid Website and HRU was compared between groups using quantile regression analysis., Results: 137 patients were included; 51 received ddMVAC and 86 GC. Baseline characteristics were similar, except lower mean age (P < 0.001) and higher proportion of ECOG-PS = 0 (P < 0.001) for ddMVAC. ddMVAC required more granulocyte-colony stimulating factor support (P < 0.001), central line placement (P = 0.017), cardiac imaging (P < 0.001), and infusion visits (P < 0.001), whereas GC required more clinic visits. ED visits were higher for ddMVAC (P = 0.048), while chemotherapy cycle delays and hospitalization days were higher for GC (P = 0.008). After adjusting for ECOG-PS and age, the cost per patient was approximately 41% lower (95%CI: 28% to 52%; P < 0.001) for GC vs. ddMVAC, which translated to a median adjusted cost savings of $7,410 (95%CI: $5,474-$9,347) per patient., Conclusions: Although excess HRU did not clearly favor one regimen, adjusting for PS and age indicated lower costs with GC vs. ddMVAC. Given the similar cumulative cisplatin delivery with both regimens, the associated values and costs supports the preferential selection of GC in the neoadjuvant setting of MIBC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To assess the effectiveness of controlled-release devices (CRDs) for providing zinc and for estimating faecal output in alpacas and sheep at pasture., Methods: The study groups of 10 alpacas and 10 sheep at pasture were paired within species and allocated at random to receive by mouth either one CRD containing chromium sesquioxide designed to function for at least 21 days or two CRDs, one containing chromium sesquioxide and the other zinc oxide designed to release over a nominal 60-day period. Faecal concentrations of chromium, zinc and ash, blood and plasma concentrations of zinc and plasma activity of alkaline phosphatase (ALP) were measured over a period of 117 days after treatment., Results: The mean faecal chromium excretion profiles suggested that the CRDs performed in a similar manner in both species, releasing chromium for nearly 30 days in alpacas and for slightly more than 30 days in sheep. Using a common predetermined release rate of chromium from the CRDs, the daily faecal outputs of alpacas and sheep were estimated to be 0.54 kg dry matter and 0.33 kg dry matter, respectively. The CRD containing zinc oxide provided after 1 week an estimated daily release rate of 40 mg zinc with a lifetime of between 60 and 70 days in both species. The additional zinc did not elicit a response in blood zinc concentrations or in plasma ALP activity., Conclusion: The CRDs were retained in the gastrointestinal tracts of the alpacas and sheep and both types functioned as expected. The CRD delivering chromium sesquioxide at a known release rate provided an estimate of faecal dry matter output over a period of almost 3 weeks and the CRD formulated to deliver supplementary zinc did so at the nominal release rate over a period of approximately 60 days in both species. These data indicated that the standard sheep CRD is applicable for use in alpacas., (© 2018 Australian Veterinary Association.)

The mean fibre diameter (MFD) of wool is the primary determinant of price, processing performance and textile quality. This study determines the primary influences on MFD as Saxon Merino sheep age, by allometrically relating MFD to fleece-free liveweight (FFLwt). In total, 79 sheep were grazed in combinations of three stocking rates and two grazing systems (GS: sheep only; mixed with Angora goats) and studied over 3 years. Measurements were made over 14 consecutive periods (Segments), including segments of FFLwt gain or FFLwt loss. Using shearing and liveweight records and dye-bands on wool, the FFLwt and average daily gain (ADG) of each sheep were determined for each segment. The mean and range in key measurements were as follows: FFLwt, 40.1 (23.1 to 64.1) kg; MFD, 18.8 (12.7 to 25.8) μm. A random coefficient restricted maximum likelihood (REML) regression mixed model was developed to relate the logarithm of MFD to the logarithm of FFLwt and other effects. The model can be written in the form of ${\rm MFD}\,{\equals}\,\rkappa \left( {{\rm GS,}\,{\rm A}{\rm ,}\,{\rm Segment}{\rm .Plot,}\,{\rm Segment,}\,{\rm ADG}} \right){\times}{\rm FFLwt}^{{\left( {\ralpha \left( {{\rm GS}} \right){\plus}\rbeta \left(\rm A \right){\plus}\rgamma \left( {{\rm Segment}{\rm .Plot}} \right)} \right)}} $ , where $\ralpha \left( {{\rm GS}} \right)\,{\equals}\,\;\left\{ {\matrix{\!\! {0.32\left( {{\rm SE}\,{\equals}\,{\rm 0}{\rm .038}} \right)\,{\rm when}\,{\rm sheep}\,{\rm are}\,{\rm grazed}\,{\rm alone}} \hfill \cr \!\!\!\!{0.49\left( {{\rm SE}\,{\equals}\,{\rm 0}{\rm .049}} \right)\,{\rm when}\,{\rm sheep}\,{\rm are}\,{\rm mixed}\,{\rm with}\,{\rm goats}} \hfill \cr } } \right.$ β(A) is a random animal effect, γ(Segment.Plot) a random effect associated with Segment.plot combinations, and κ a constant that depends on GS, random animal effects, random Segment.plot combination effects, Segment and ADG. Thus, MFD was allometrically related to the cube root of FFLwt over seasons and years for sheep, but to the square root of FFLwt for sheep grazed with goats. The result for sheep grazed alone accords with a primary response being that the allocation of nutrients towards the cross-sectional growth of wool follicles is proportional to the changes in the skin surface area arising from changes in the size of the sheep. The proportionality constant varied systematically with ADG, and in sheep only grazing, was about 5 when sheep lost 100 g/day and about 6 when sheep gained 100 g/day. The proportionality constant did not systematically change with chronological age. The variation in the allometric coefficient between individual sheep indicates that some sheep were more sensitive to changes in FFLwt than other sheep. Key practical implications include the following: (a) the reporting of systematic increases in MFD with age is likely to be a consequence of allowing sheep to increase in size during shearing intervals as they age; (b) comparisons of MFD between sheep are more likely to have a biological basis when standardised to a common FFLwt and not just to a common age;, ((c) wool quality (MFD, staple strength) are most likely to be optimised in management systems that maintain constant FFLwt of adult sheep within and between years.)

Objective: To quantify if, and to what extent, permanent incisor wear differed with age of goat and farm of origin on commercial Australian Angora goat farms., Design: Observations were made on three Angora goat farms in the wheat-sheep zone of Victoria, each managed according to the farmer's practices. Farmers provided a representative flock of does., Methods: The proportion and pattern of wear of permanent incisors were recorded and percentage wear calculated. After log(y + 10) transformation, a parsimonious general linear model was developed to relate wear to farm and age, with age considered as a continuous variate., Results: The range in wear of the permanent incisors was 0-100%. For each farm, the most parsimonious model for permanent first incisor wear and average wear of all permanent incisors was a separate straight line relating the transformed incisor wear to the age of doe. The models accounted for 66-73% of variance. On each farm the incisor wear was similar and low for ages up to approximately 4 years. On all farms, the amount of incisor wear increased dramatically with age, although the rate of increase differed with each farm., Conclusions: Permanent incisor wear increased with age of goat and differed with farm of origin. Angora goat farmers need to be aware of the potential for incisor wear to affect doe production and health., (© 2015 Australian Veterinary Association.)

Objective: To investigate the effects of the timing and duration of eruption of the first permanent incisors, live weight, sex and other factors on contemporaneous live weight gain in Angora goats., Design: Goats were previously part of a pen study on the effects of energy intake of Angora does during pregnancy and lactation on kid development. The design was 3 levels of nutrition in mid-pregnancy by 2 levels of postnatal nutrition in 17 randomised blocks., Methods: Artificial insemination, ultrasound examination and feeding does in pens enabled accurate conduct of the study. After weaning, goats were grazed in sex groups. Live weight change between 14 and 20 months of age was related to deciduous first incisor loss and permanent first incisor development and other attributes assessed before the study., Results: Live weight change was related to the elapsed time for first permanent incisors to commence eruption and to the length of time for first permanent incisors to erupt. This response was affected by sex. Over summer and autumn, entire males with short eruption intervals gained 2-3 kg more than entire males with long eruption intervals. Females that reached first permanent incisor eruption by mid-summer had a live weight gain of 3 kg more than those that reached the same development 3 months later., Conclusions: Live weight change in yearling Angora goats was associated with the process of first permanent incisor eruption. In females, live weight gain was greater when first permanent incisor eruption was earlier. In males, live weight gain was greater when first permanent incisor eruption was faster., (© 2013 The Authors. Australian Veterinary Journal © 2013 Australian Veterinary Association.)

Objective: To investigate the effects of live weight, sex and other factors on deciduous (first incisor) loss and permanent first incisor development in Angora goats., Design: Goats were part of a pen study on the effects of energy intake in Angora does during pregnancy and lactation on kid growth and development. The design was three levels of nutrition in mid-pregnancy × two levels of postnatal nutrition in 17 randomised blocks., Methods: Conception times were calculated by using artificial insemination, with ultrasound examination 43 days after insemination. Does were fed different amounts of a formulated diet in their pens. After weaning, goats were grazed in sex groups. Deciduous first incisor loss and permanent first incisor development were recorded at 11 time points from 14 to 20 months of age., Results: For each sex, the time for visible eruption and full development of permanent first incisor declined linearly with increased live weight by 5.9 and 5.4 days/kg live weight, respectively. The time to reach similar development stages for first permanent incisors eruption was 3 months longer for the lightest animals compared with the heaviest animals. Date of birth, birth weight, doe age, growth rates, mid-pregnancy and postnatal nutrition, parity, day of weaning and weaning weight had no detectable effect., Conclusions: The results explain much of the substantial range in reported first permanent incisor eruption dates for small ruminants and have application in ageing of goats, marketing of kids for meat, in the selection of animals for breeding flocks and in educational material., (© 2011 The Authors. Australian Veterinary Journal © 2011 Australian Veterinary Association.)

Objective: To investigate factors associated with low vitamin D status of alpacas at pasture in southern Australia., Design: A 2-year survey of alpacas from two farms in South Australia and three in Victoria. Blood samples were collected from 20 to 30 alpacas on each farm on five occasions each year. Breed, gender, age and fleece colour of animals were recorded., Method: Blood samples were assayed for plasma 2.5-hydroxycholecalciferol (25-OH D(3)) and plasma inorganic phosphorus (Pi). Data sets from 802 animal samples were analysed by multiple regression to determine variables associated with low vitamin D status of alpacas. The relationship between plasma 25-OH D(3) and plasma Pi was also investigated., Results: Vitamin D status was significantly affected by month of sampling, with low values in late winter and high values in summer. Plasma vitamin D concentrations increased with age, were higher in alpacas with light fleeces than in those with dark fleeces and were also higher in the Suri than in the Huacaya breed. Plasma Pi concentrations were generally lower in alpacas with plasma 25-OH D(3) values < 25 nmol/L., Conclusions: Young alpacas with dark fleeces are most at risk from vitamin D insufficiency in late winter in southern Australia. The present study indicates that plasma Pi values are not a reliable indicator of vitamin D status of alpacas as assessed by plasma 25-OH D(3) concentrations.

Unlabelled: Body condition scoring is widely used for sheep and cattle but the practice is included in only one Code of Practice for the welfare of goats in Australia. There is no published scientific evidence to support or defend its use in the assessment of welfare risks to farmed goats., Procedure: The significance of stocking rate, grazing system, body condition score (CS) and live weight were investigated in explaining the risk of mortality of individual and flocks of grazing Angora goats from hypothermia following a severe weather event in April. This event occurred 5 weeks after shearing the goats. Angora goats and Saxon Merino sheep were grazed alone, or mixed together in equal numbers at each of three stocking rates., Results: There was no mortality amongst Angora goats provided they grazed at the lowest stocking rate even when their CS was < or = 2.0. Mortality in flocks of Angora goats was most related to the CS reached during the preceding 2 months. For flocks of Angora goats there was no mortality at CS > or = 2.5 and mortality increased sharply at mean CS < 2.0. For individual Angora goats, mortality increased as CS declined and stocking rate and grazing combinations were additive in effect on mortality. Grazing with sheep increased mortality of Angora goats at higher stocking rates. The individual goat mortality rate was not dependent on individual plot effects suggesting that these results are applicable widely. Live weight loss was not related to mortality rates of goats once CS had been accounted for., Conclusion: It was concluded that CS and stocking rate were highly significant determinants of welfare risk in Angora goats.

The authors tested effects of a 10-week group cognitive-behavioral stress management intervention among 100 women newly treated for Stage 0-II breast cancer. The intervention reduced prevalence of moderate depression (which remained relatively stable in the control condition) but did not affect other measures of emotional distress. The intervention also increased participants' reports that having breast cancer had made positive contributions to their lives, and it increased generalized optimism. Both remained significantly elevated at a 3-month follow-up of the intervention. Further analysis revealed that the intervention had its greatest impact on these 2 variables among women who were lowest in optimism at baseline. Discussion centers on the importance of examining positive responses to traumatic events--growth, appreciation of life, shift in priorities, and positive affect-as well as negative responses.

Objective: This study examined the effects of a cognitive-behavioral stress management (CBSM) group intervention on serum cortisol levels in women being treated for stage I or II breast cancer., Methods: Participants were randomly assigned to undergo a 10-week intervention (N = 24) within 8 weeks after surgery or were placed on a waiting list (N = 10). Cortisol was assessed by means of a radioimmunoassay of blood samples collected at the same time of day just before the start of the intervention and immediately after its completion. The women also reported the degree to which breast cancer had made positive contributions to their lives., Results: Intervention participants showed increased benefit finding and reduced serum cortisol levels, whereas control subjects experienced neither change. Path analysis suggested that the effect of CBSM on cortisol was mediated by increases in benefit finding., Conclusions: These findings suggest that positive growth enhanced during a time-limited intervention can influence physiological parameters such as cortisol among women with early stage breast cancer.

Cashmere goats and Merino sheep were grazed together at 7.5 animals per ha on annual rye grass and clover pasture in southern Victoria, a winter rainfall area. Intake of parasitic larvae was measured in oesophageal extrusa samples collected from 2 animals of each species, 4 times in one week, on 7 occasions between mid-March (autumn) and mid-June (winter). Pasture contamination with larvae was measured at the same times. The number of larvae per kg of green grass was lower than on green clover; the most heavily contaminated portion of the pasture was the mat of dead herbage on the ground. The diet selected by goats contained more green grass and dead herbage and less clover that that of sheep (P < 0.01). Goats ingested 643 infective trichostrongylid larvae per kg dry matter intake (DMI) versus 274 per kg DMI for sheep in autumn, increasing to 1892 versus 1143 in early winter. The heavier trichostrongylid burdens of goats compared with sheep, when grazed together, are due in part to greater rates of infection consequent on different grazing patterns as well as greater susceptibility to infection.