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Background: Interaction between nutrition and reproduction has been established to play an important role in reproductive performance of animals. Zinc is considered to be an essential element required for reproduction. The present study was conducted to evaluate the efficiency of nano zinc (NZn) as feed supplementation on reproductive performance of Assam Hill goats. Methods: A total of twenty-four numbers of 7 days post kidding doe maintained at Goat Research Station, Assam Agricultural University, Burnihat were randomly selected and divided into 4 groups comprising 6 animals in each group. The control group animals were fed with basal diet without zinc supplementation however, all the animals of the treatment groups received 25 mg NZn, 35 mg NZn and 50 mg NZn/kg concentrate mixture with basal diet for a period of three months. Does were bred naturally at 24 hours from the onset of oestrus and confirmed for pregnancy after two months. Parturition behaviour was observed closely from two days before the expected date of kidding upto the period of placental expulsion. Result: Supplementation of 50 mg NZn to the basal diet of postpartum Assam Hill Goat significantly improved the reproductive performance by decreasing postpartum oestrus interval and increasing conception rate (83.33%). [ABSTRACT FROM AUTHOR]

Background: Postpartum anoestrus is the most devastating cause of the dairy farming which causes more economic losses to the farmers. The present study was conducted to record the incidence of postpartum anoestrus and to evolve a suitable therapeutic regime for addressing postpartum anoestrus in Lakhimi cows. Methods: A total of 1000 Lakhimi cows maintained in different villages of Assam were selected and the incidence rate was recorded on the basis of breeding records provided by the farmers, per-rectal examination and ultrasonography screening of genital organ. To study the effect of hormonal and nutritional interventions in post partum anoestrus cows, the cows were divided randomly into seven groups comprising twelve animals in each group. The different treatment regimes were Hydroxyprogesterone caproate + eCG, Clomiphene citrate alone, Clomiphene citrate + Mineral mixture, GnRH analogue alone, GnRH analogue + Mineral mixture, Mineral mixture alone and control. The response to different treatment regimes was based on oestrus response, mean interval from the end of treatment to onset of oestrus and conception rate. Result: The incidence of postpartum anoestrus was found to be 20.60%. Clomiphene citrate + Mineral mixture administration regime brought about the highest oestrus induction response (100.00%) and conception rate (66.67%). [ABSTRACT FROM AUTHOR]

Many low-threshold experiments observe sharply rising event rates of yet unknown origins below a few hundred eV, and larger than expected from known backgrounds. Due to the significant impact of this excess on the dark matter or neutrino sensitivity of these experiments, a collective effort has been started to share the knowledge about the individual observations. For this, the EXCESS Workshop was initiated. In its first iteration in June 2021, ten rare event search collaborations contributed to this initiative via talks and discussions. The contributing collaborations were CONNIE, CRESST, DAMIC, EDELWEISS, MINER, NEWS-G, NUCLEUS, RICOCHET, SENSEI and SuperCDMS. They presented data about their observed energy spectra and known backgrounds together with details about the respective measurements. In this paper, we summarize the presented information and give a comprehensive overview of the similarities and differences between the distinct measurements. The provided data is furthermore publicly available on the workshop’s data repository together with a plotting tool for visualization.

The present study was conducted on a total of 909 crossbred cows maintained in various private farms from Kamrup, Darrang and Lakhimpur districts of Assam. Breeding records provided by the farmers and characteristic genital changes detected on per rectum examination of 133 reported infertile cows were analyzed. The study revealed that the incidence of infertility due to different types of reproductive disorders was 14.63 per cent in cross bred cow under field conditions. Common clinically detectable reproductive disorders were repeat breeding with uterine infection, repeat breeding without uterine infection, true anoestrus and silent oestrus with the percentage frequencies of 36.09, 23.30, 20.30 and 17.29 respectively when estimated out of total number of infertile cows. Less frequent reproductive disorders were pyometra, ovarian cyst, infantile genitalia and ovario-bursal adhesion occurring in the frequencies of 36.09, 23.30, 20.30 and 17.29 per cent respectively. Irrespective of type the incidence of anoestrus and repeat breeding was 37.59 and 59.39 per cent respectively. Palpable corpus luteum was present in the ovary of silent oestrous cows but totally absent in cows affected with true anoestrus. Mucopurulent vaginal discharge was a distinct clinically detectable genital characteristic observed in 62.50 per cent repeat breeder cows with uterine infection. Of the infertile cows 53.38 per cent had body condition score between 2.5 and 3.5 and 46.61 per cent had the score less than 2.5. Out of repeat breeder cows with uterine infection 43.66 per cent had good body condition and 27.41 per cent poor body condition. Level of serum calcium, zinc, leptin, ghrelin and IGF-1 did not vary significantly between types of infertility. Level of phosphorus and iron was lower in cows affected with repeat breeding due to infection. Serum oestrogen level remained low in cows affected with silent oestrus and true anoestrus while level of progesterone was higher in cows affected with silent oestrus. [ABSTRACT FROM AUTHOR]

The efficacy of different tapioca varieties on larval growth and quantitative cocoon characters of eri silkworm revealed that the larvae reared on H-97 variety performed better with shorter larval duration in respect of larval growth parameters such as larval weight (full grown and mature), silkgland weight, silkgland tissue somatic index, effective rate of rearing and cocoon parameters viz., cocoon weight, shell weight and shell ratio compared to other varieties and spring rearing accounted better for larval growth and cocoon characters. [ABSTRACT FROM AUTHOR]

Sericulture is an agro based labour intensive industry providing gainful employment mostly for rural people. Sericulture comprises cultivation of four varieties of silkworm mainly Mulberry, Eri, Muga and Tassar. Though, all the four major varieties of silk are reared in Assam, eri silk occupies the prime position in the sericulture scenario of the state. The present study was carried out in Jorhat district of Assam. The district consists of 3 sub-divisions and out of which two sub-divisions namely Jorhat Sadar and Titabar were selected. Among these, two villages were selected from each sub-division by simple random sampling technique and a sample of eighty respondents was selected from these four villages. The study revealed that nearly sixty one per cent of the eri rearers exhibited medium level of extent of adoption, followed by twenty one per cent exhibited low level of extent of adoption, while about eighteen per cent of the rearers exhibited high level of extent of adoption respectively. The perusal of data revealed that out of ten dependent variables, five variables viz, age, education, size of operational land holding, annual family income, risk bearing of the rearers was positively and significantly related with the extent of adoption of scientific eri culture practices at 0.01 level of probability. [ABSTRACT FROM AUTHOR]

The study on incidence and intensity of attack of Ariadne merione C. infesting castor in the agro climatic condition of Assam revealed that the insect pest made its appearance from the month of April and continued till February. The incidence and intensity of attack of the pest gradually increased from the month of April and reach peak in October and thereafter it deceases with no incidence in the month of March. The correlation study on incidence and intensity of attack of the insect pest with weather parameters revealed that bright sunshine hour has positive and significant relationship with incidence and positive and non significant relationship with intensity of attack. The relationship with maximum temperature, morning and evening relative humidity was positive and non significant while it was negative and non significant with number of rainy days and total rain fall in respect of both incidence and intensity of attack. The regression analysis revealed that 99.1 percent variation in incidence and 98.8 percent variation in intensity of attack of the insect pest were influenced by the combine effect of various weather parameters. [ABSTRACT FROM AUTHOR]

The study undertaken at Assam Agricultural University, Jorhat (Assam) on effect of oviposition devices and mating durations on oviposition, fecundity and hatchability of muga silkworm revealed that oviposition period of muga silk moth continues for a maximum of 7 days irrespective of mating duration and oviposition devices. A period of 3-5 hours mating duration is optimum for maximum egg laying of muga silk moth. In addition to common practices of egg laying preparation of muga silk moth on Kharika, the bio-degradable news paper, tree twig and rice straw made coupling devices could be effectively used for quality egg (seed) production of muga silkworm. [ABSTRACT FROM AUTHOR]

The present study was conducted on 400 White Pekin duck reared in intensive system at Udalguri district of Assam under tribal sub plan project. The mean body weight of White Pekin duck at 8 week of age was 2480.33 ± 76.40 and ranged from 2280 - 2550 gram and at 10 week the weight was 2720.47 ±59.32 grams and ranged from 2650 - 2800 gram. The benefit cost ratio was recorded as 1.78. The newly introduced duck was highly accepted by the people and horizontal spread of the breed is in progress throughout the distric. Introduction: White Pekin duck also known as broiler duck is famous for its rapid growth rate. At seven to eight weeks of age the duck attain around three kg (Wu-son, 1973; Leeson et al., 1976 and Adams et al., 1983) therefore, it can be marketed at this age. This figure is much higher than the average weight normally obtained from local ducks and even from broiler chickens over the same period of growth. The introduction of this strain of duck was quite recent in Assam, but its popularity much higher in other parts of the country. [ABSTRACT FROM AUTHOR]

In many regions of the world, significant data collection, analysis, and availability on comorbidity and fatality incidents caused by COVID-19 during the lockdown period (2020-2022) is rare. This is especially true for hospitals and COVID treatment facilities in India. This lack of understanding impedes the development of appropriate treatment options, potentially resulting in inferior planning, patient recovery results, and a load on healthcare resources. This project intends to bridge the gap and enhance patient care in Assam, India, in light of the COVID pandemic. Furthermore, this study aims to determine baseline patient characteristics associated with an elevated risk of death among hospitalized COVID-19 patients in Assam. We employed machine learning (ML) and deep learning (DL) approaches to discover hidden patterns in patient data that could predict which individuals are more sensitive to severe consequences. This knowledge has the potential to transform patient care by allowing doctors to personalize treatment plans and prioritize resources for individuals who are most at risk. A retrospective observational analysis was performed using data from 5329 individuals hospitalized with SARS-CoV-2 illness between April and December 2021. ML and DL algorithms could be used to examine patient characteristics and identify risk factors for death (in this case, 554). We expect this to help us better understand the risk factors for in-hospital death among COVID19 patients in Assam. The findings could be useful in building risk assessment tools to guide patient care., (© 2024 The Authors.)

Background: Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest., Methods: Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell-inflamed gene expression profile (Tcell inf GEP) and 11 other gene signatures were evaluated by RNA sequencing. TMB, hotspot mutations in PIK3CA (oncogene), and deleterious mutations in PTEN and TP53 (tumor suppressor genes) were evaluated by whole-exome sequencing (WES)., Results: 93 and 79 patients were included in the RNA-sequencing-evaluable and WES-evaluable populations, respectively. No statistically significant associations were observed between any of the RNA-sequencing signature scores and objective response rate or progression-free survival. Area under the receiver operating characteristic curve values for response ranged from 0.39 to 0.54; all 95% CIs included 0.50. Responses were seen regardless of TMB (≥175 or <175 mutations/exome) and mutation status. There were no correlations between Tcell inf GEP and TMB, Tcell inf GEP and microvessel density (MVD), or MVD and TMB., Conclusions: This analysis demonstrated efficacy for lenvatinib plus pembrolizumab regardless of biomarker status. Results from this study do not support clinical utility of the evaluated biomarkers. Further investigation of biomarkers for this regimen is warranted., Trial Registration Number: NCT02501096., Competing Interests: Competing interests: VM is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748. Study support (all funding to institution)/unpaid consultancy/advisory board membership from AstraZeneca, Clovis, Duality, Eisai, Faeth, Genentech, GSK, Immunocore, iTEOS, Kartos, Karyopharm, Moreo, Morphosys, MSD, Novartis, Takeda, and Zymeworks. MHT received honoraria for consulting/advisory board participation from Bristol-Myers Squibb, Eisai Inc, Novartis, Merck & Co., Inc., Pfizer, Bayer, Sanofi/Genzyme, Regeneron, LOXO Oncology, Blueprint Medicines, Immune-onc, Exelixis, and Cascade Prodrug. MHT received honoraria for participation in speakers' bureaus from Bristol-Myers Squibb, Eisai Inc, Blueprint Medicines, and Merck & Co., Inc. Research funding to Dr Taylor’s institution was provided by Bristol-Myers Squibb, Eisai, Merck & Co., Inc., Pfizer, Immune-Onc, and Simcha. CA: Clinical trial funding (to institution): AbbVie, Artios Pharma, AstraZeneca, Clovis, and Genentech/Roche; Advisory board (fees): Merck; Advisory board (no fees): Blueprint Medicine; Data Monitoring Committee: AstraZeneca; Leadership role: GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) and NRG Oncology, Board of Directors (unpaid). CA is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748. ALC: Honoraria: Amgen; Expert Testimony: Department of Justice. MSB: Consulting/advisory board member (honoraria paid to me): Eisai Inc, Exelixis, Loxo Oncology, Eli Lilly, and Bayer Pharmaceuticals. CDS: Nothing to disclose. ZAC, AL, RC, PJ, and RO: Employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholders in Merck & Co., Inc., Rahway, NJ, USA. LS: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. LD, JM, and CED: Employees of Eisai Inc., Nutley, NJ, USA. YM: Employee of Eisai Co. Ltd., Tsukuba, Japan, and a stockholder in Eisai Co., Ltd. MJM: Nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ralstonia solanacearum is a rod-shaped phytopathogenic bacterium that causes lethal wilt disease in many plants. On solid agar growth medium, in the early hour of the growth of the bacterial colony, the type IV pili-mediated twitching motility, which is important for its virulence and biofilm formation, is prominently observed under the microscope. In this study, we have done a detailed observation of twitching motility in R. solanacearum colony. In the beginning, twitching motility in the microcolonies was observed as a density-dependent phenomenon that influences the shape of the microcolonies. No such phenomenon was observed in Escherichia coli, where twitching motility is absent. In the early phase of colony growth, twitching motility exhibited by the cells at the peripheral region of the colony was more prominent than the cells toward the center of the colony. Using time-lapse photography and merging the obtained photomicrographs into a video, twitching motility was observed as an intermittent phenomenon that progresses in layers in all directions as finger-like projections at the peripheral region of a bacterial colony. Each layer of bacteria twitches on top of the other and produces a multilayered film-like appearance. We found that the duration between the emergence of each layer diminishes progressively as the colony becomes older. This study on twitching motility demonstrates distinctly heterogeneity among the cells within a colony regarding their dynamics and the influence of microcolonies on each other regarding their morphology., (© 2023 Wiley-VCH GmbH.)

Catalysis by trivalent nucleophilic organophosphines has emerged as an essential tool in organic synthesis. Several new organic transformations promoted by phosphines substantiate and complement the existing synthetic chemistry tools. Mere design of the substrate and reagent combinations has introduced new modes of reactivity patterns, which are otherwise difficult to achieve. These design considerations have led to the rapid build-up of complex molecular entities and laid a solid foundation to synthesise bioactive natural products and pharmaceuticals. This article presents an overview of some of the conceptual advances, including our contributions to nucleophilic organophosphine chemistry. The scope, limitations, mechanistic insights, and applications of these metal-free transformations are discussed elaborately.

Antibiotics have emerged as ground-breaking medications for the treatment of infectious diseases, but due to the excessive use of antibiotics, some drugs have developed resistance to microorganisms. Because of their structural complexity, most antibiotics are excreted unchanged, polluting the water, soil, and natural resources. Additionally, food items are being polluted through the widespread use of antibiotics in animal feed. The normal concentrations of antibiotics in environmental samples typically vary from ng to g/L. Antibiotic residues in excess of these values can pose major risks the development of illnesses and infections/diseases. According to estimates, 300 million people will die prematurely in the next three decades (by 2050), and the WHO has proclaimed "antibiotic resistance" to be a severe economic and sociological hazard to public health. Several antibiotics have been recognised as possible environmental pollutants (EMA) and their detection in various matrices such as food, milk, and environmental samples is being investigated. Currently, chromatographic techniques coupled with different detectors (e.g., HPLC, LC-MS) are typically used for antibiotic analysis. Other screening methods include optical methods, ELISA, electrophoresis, biosensors, etc. To minimise the problems associated with antibiotics (i.e., the development of AMR) and the currently available analytical methods, electrochemical platforms have been investigated, and can provide a cost-effective, rapid and portable alternative. Despite the significant progress in this field, further developments are necessary to advance electrochemical sensors, e.g., through the use of multi-functional nanomaterials and advanced (bio)materials to ensure efficient detection, sensitivity, portability, and reliability. This review summarises the use of electrochemical biosensors for the detection of antibiotics in milk/milk products and presents a brief introduction to antibiotics and AMR followed by developments in the field of electrochemical biosensors based on (i) immunosensor, (ii) aptamer (iii) MIP, (iv) enzyme, (v) whole-cell and (vi) direct electrochemical approaches. The role of nanomaterials and sensor fabrication is discussed wherever necessary. Finally, the review discusses the challenges encountered and future perspectives. This review can serve as an insightful source of information, enhancing the awareness of the role of electrochemical biosensors in providing information for the preservation of the health of the public, of animals, and of our environment, globally.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The open-label phase Ib/II Study 111/KEYNOTE-146 of daily lenvatinib 20 mg plus pembrolizumab 200 mg once every 3 weeks showed promising efficacy and tolerable safety in patients with previously treated advanced endometrial carcinoma (EC; primary data cutoff date: January 10, 2019). This updated analysis reports long-term follow-up efficacy and safety data from 108 patients with previously treated EC included in the primary analysis. End points included objective response rate, duration of response, progression-free survival, overall survival, and safety. Investigators performed tumor assessments per immune-related RECIST. At the updated data cutoff date (August 18, 2020), the median study follow-up duration was 34.7 months (95% CI, 30.9 to 41.2), the objective response rate was 39.8% (95% CI, 30.5 to 49.7), and the median duration of response was 22.9 months (95% CI, 10.2 to not estimable). The median progression-free survival and overall survival were 7.4 months (95% CI, 5.2 to 8.7) and 17.7 months (95% CI, 15.5 to 25.8), respectively. Treatment-related treatment-emergent adverse events of any grade occurred in 104 (96.3%) patients. The most common grade ≥ 3 treatment-related treatment-emergent adverse events were hypertension (33.3%), elevated lipase (9.3%), fatigue (8.3%), and diarrhea (7.4%). The results demonstrate extended efficacy and tolerability of lenvatinib plus pembrolizumab in this cohort of patients with previously treated advanced EC.

We describe a metal-free strategy to access various α-arylidene cyclopenta[ b ]indoles via phosphine-catalysed (3 + 2) annulation of α,β-ynones and 3-nitroindoles. For the first time, the rearomatisation of the indole nucleus was observed in such an annulative transformation. The method was extended to the synthesis of an antimalarial natural product, bruceolline E.

3-Hydroxyquinoline-4(1 H )-ones (3HQs) are privileged structural motifs. The current methods for their synthesis necessitate strongly acidic or basic conditions, which hamper the generality and practicality. Here, we describe phosphine-mediated redox transformation of easily accessible 1-(2-nitroaryl)prop-2-ynones to 3HQs. Besides establishing a new entry to the synthesis of 3HQs under neutral conditions, this method is the first formal intramolecular oxyamination of α,β-ynones. The synthetic utility of this method is demonstrated in the total synthesis of japonine, its analogs, and rare quinoline derivatives.

Study 309/KEYNOTE-775 is a phase 3 open-label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with progression after platinum-based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression-free survival (PFS) and overall survival (OS) in all-comers (ie, regardless of mismatch repair [MMR] status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m 2 Q3W or paclitaxel 80 mg/m 2 QW [3 weeks on/1 week off]). Primary endpoints were PFS by blinded independent central review per RECIST version 1.1 and OS. One hundred four patients were randomized in Japan (data cutoff, October 26, 2020; median follow-up, 11.8 [range, 1.1-26.9] months). Hazard ratios (HRs) for PFS with lenvatinib plus pembrolizumab versus TPC were 1.04 (95% CI, 0.63-1.73) in patients with pMMR and 0.81 (0.50-1.31) in all-comers. Hazard ratios for OS were 0.74 (0.41-1.34) with pMMR and 0.59 (0.33-1.04) for all-comers. Adverse events were manageable and led to discontinuation of one/both study drugs in 36.5% of patients in the lenvatinib plus pembrolizumab group versus 7.8% in the TPC group. Similar to the global Study 309/KEYNOTE-775 results, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum-based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

This article reports a facile fabrication of a highly sensitive enzyme-free sweat glucose sensor over Whatman filter paper substrate employing a dual-step pencil and pen approach. Initially, two pencil-drawn electrodes (PDEs) are obtained on the filter paper through the manual abrasion of an 8B graphite pencil. Then, the sensing layer is drawn over one of the PDEs using a custom-made copper (Cu) nanoparticle ink (CuNP-ink) pen to form copper nanoparticle ink decorated PDE (CuNP-ink/PDE) which serves as a working electrode, while the other PDE is drawn with silver conductive ink (Ag-ink) pen to form reference electrode. The developed CuNP-ink/PDE is composed of 43.5% of metallic Cu nanoparticles, inducing a highly crystalline and conductive nature, thus promoting fast electron transfer during glucose electrooxidation. The developed sensor offers a sensitivity of 2691.7 μAmM -1 cm -2 , a detection limit of 0.5 μM, a linear range of 1.2-40 μM, and a fast response time of ∼ 1.5 s. Besides, the sensor measurements are stable, reproducible, and selective in glucose sensing. Also, the reliability of the sensor is tested by comparing its performance with a UV-Visible spectrophotometer for proving its efficacy in sweat glucose detection. Experimental results evince the effectiveness of the designed sensor for glucose detection in human sweat., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Amarprit Singh reports financial support was provided by Department of Science and Technology, Govt. of India., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation methods are frequently inaccurate and problematic. Multiple strategies are being pursued to disentangle responsible mechanisms. The objective of this work is to evaluate the feasibility of using insights gained from independent virtual experiments on two model systems to begin unraveling responsible mechanisms. The virtual culture is a software analog of hepatocytes in vitro, and the virtual human maps to hepatocytes within a liver within an idealized model human. Mobile objects (virtual compounds) map to amounts of xenobiotics. Earlier versions of the two systems achieved quantitative validation targets for intrinsic clearance (virtual culture) and hepatic clearance (virtual human). The major difference between the two systems is the spatial organization of the virtual hepatocytes. For each pair of experiments (virtual culture, virtual human), hepatocytes are configured the same. Probabilistic rules govern virtual compound movements and interactions with other objects. We focus on highly permeable virtual compounds and fix their extracellular unbound fraction at one of seven values (0.05-1.0). Hepatocytes contain objects that can bind and remove compounds, analogous to metabolism. We require that, for a subset of compound properties, per-hepatocyte compound exposure and removal rates during culture experiments directly predict corresponding measures made during virtual human experiments. That requirement serves as a cross-system validation target; we identify compound properties that enable achieving it. We then change compound properties, ceteris paribus, and provide model mechanism-based explanations for when and why measures made during culture experiments under- (or over-) predict corresponding measures made during virtual human experiments. The results show that, from the perspective of compound removal, the organization of hepatocytes within virtual livers is more efficient than within cultures, and the greater the efficiency difference, the larger the underprediction. That relationship is noteworthy because most in vitro-to-in vivo extrapolation methods abstract away the structural organization of hepatocytes within a liver. More work is needed on multiple fronts, including the study of an expanded variety of virtual compound properties. Nevertheless, the results support the feasibility of the approach and plan., Competing Interests: The authors declare no competing interests. GEPR’s affiliation with Tempus Dictum Inc. does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear., Methods: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen to receive either lenvatinib (20 mg, administered orally once daily) plus pembrolizumab (200 mg, administered intravenously every 3 weeks) or chemotherapy of the treating physician's choice (doxorubicin at 60 mg per square meter of body-surface area, administered intravenously every 3 weeks, or paclitaxel at 80 mg per square meter, administered intravenously weekly [with a cycle of 3 weeks on and 1 week off]). The two primary end points were progression-free survival as assessed on blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival. The end points were evaluated in patients with mismatch repair-proficient (pMMR) disease and in all patients. Safety was also assessed., Results: A total of 827 patients (697 with pMMR disease and 130 with mismatch repair-deficient disease) were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median progression-free survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.50 to 0.72; P<0.001; overall: 7.2 vs. 3.8 months; hazard ratio, 0.56; 95% CI, 0.47 to 0.66; P<0.001). The median overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months; hazard ratio for death, 0.68; 95% CI, 0.56 to 0.84; P<0.001; overall: 18.3 vs. 11.4 months; hazard ratio, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy., Conclusions: Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. (Funded by Eisai and Merck Sharp and Dohme [a subsidiary of Merck]; Study 309-KEYNOTE-775 ClinicalTrials.gov number, NCT03517449.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: Tyrosine kinase inhibitors have shown activity in osteosarcoma and might enhance the efficacy of chemotherapy. We aimed to determine the recommended phase 2 dose and antitumour activity of lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma., Methods: This multicentre, open-label, multicohort, phase 1/2 trial was done at 17 hospitals in six countries. Eligible patients were aged 2-25 years, had relapsed or refractory osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Lansky play-performance score or Karnofsky performance score of 50% or higher, up to one previous VEGF or VEGF receptor-targeted therapy, and a life expectancy of at least 3 months. This study includes a combination dose-finding phase 1 part (cohort 3A) and a phase 2 combination expansion in patients with osteosarcoma (cohort 3B). Lenvatinib was administered orally at a starting dose of 11 mg/m 2 per day, capped at 24 mg per day, and etoposide (100 mg/m 2 per day) plus ifosfamide (3000 mg/m 2 per day) were administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. Lenvatinib monotherapy continued after these five cycles until disease progression, toxic effects, or patient choice to discontinue. The phase 1 primary endpoint was to determine the recommended phase 2 dose by evaluating dose-limiting toxicity and the phase 2 primary endpoint was progression-free survival at 4 months. Progression-free survival was measured in the full analysis set, which included all patients enrolled for efficacy outcomes; safety was assessed in all patients who received any study drug. This study is registered with ClinicalTrials.gov, NCT02432274., Findings: 30 patients were screened for enrolment into cohort 3A between May 9, 2016, and June 3, 2019, and 22 patients for enrolment into cohort 3B between Sept 13, 2018, and July 18, 2019. Eight patients from cohort 3A and two from cohort 3B were ineligible for enrolment in the study. In phase 1, dose-limiting toxicities were observed in three patients (one in the lenvatinib 11 mg/m 2 combination group and two in the 14 mg/m 2 combination group) and the recommended phase 2 dose was determined as lenvatinib 14 mg/m 2 per day (with daily dose cap of 24 mg) and etoposide 100 mg/m 2 per day plus ifosfamide 3000 mg/m 2 per day administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. 35 patients from phase 1 (cohort 3A; n=15) and phase 2 (cohort 3B; n=20) were treated at the recommended phase 2 dose and their results were pooled. Progression-free survival at 4 months was 51% (95% CI 34-69) in 18 of 35 patients per the binomial estimate. The most common grade 3-4 treatment-emergent adverse events were neutropenia (27 [77%] of 35), thrombocytopenia (25 [71%]), anaemia (19 [54%]), and decreased white blood cell count (19 [54%]). 26 [74%] of 35 patients had serious treatment-emergent adverse events and no treatment-related deaths occurred., Interpretation: Lenvatinib with etoposide plus ifosfamide shows promising antitumour activity with no new safety signals in patients with refractory and relapsed osteosarcoma. These findings warrant further investigation in an ongoing randomised phase 2 study (NCT04154189)., Funding: Eisai and Merck Sharp & Dohme., Competing Interests: Declaration of interests NG reports fees from Eisai for presenting the study results at a scientific congress meeting. SH-N reports institutional study and grant funding from Eisai and an unpaid leadership role as cochair of the Pediatric Cancer Data Commons. SGM reports personal fees from Bayer for an educational event and personal fees from Loxo Oncology, Bayer, and Eusa Pharma for participating on an advisory board. SJS reports personal consulting fees from GSK for participating on an advisory board. CEO, CH, and LD are employees of Eisai. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The combination of lenvatinib plus pembrolizumab has shown efficacy in treatment of advanced endometrial carcinoma (that is not microsatellite instability-high or mismatch repair deficient) following prior systemic therapy in any setting in the open-label, single-arm, phase Ib/II Study 111/KEYNOTE-146. With the exception of hypothyroidism, the safety profile of the combination was comparable to that of each monotherapy. Given the medical complexity and fragility of patients with endometrial carcinoma, further characterization of adverse reactions (ARs) associated with treatment will help health care professionals to optimize treatment with lenvatinib plus pembrolizumab combination therapy., Patients and Methods: In Study 111/KEYNOTE-146, patients received lenvatinib at a starting dose of 20 mg orally once daily and pembrolizumab 200 mg intravenously every 3 weeks. Selected ARs (hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria) were chosen for detailed post hoc analyses., Results: Median times to first onset of the selected ARs in this analysis all occurred within the first 10 weeks of treatment. Of the selected ARs, grade ≥3 severity of fatigue, hypertension, and nausea occurred in ≥5% of patients. Overall incidence of hypothyroidism was 51%, primarily of grade 2 severity (46%). Most of the ARs assessed were managed with a combination of study drug dose modifications and concomitant medications., Conclusion: No new safety signals were identified and the toxicity profile in this study was manageable with supportive medications, dose interruptions, and/or lenvatinib dose reductions. This analysis provides AR management guidance for patients with endometrial cancer receiving lenvatinib plus pembrolizumab combination therapy., Implications for Practice: Lenvatinib plus pembrolizumab has shown efficacy in the treatment of patients with advanced endometrial carcinoma (that is, not microsatellite instability-high or mismatch repair deficient) following at least one prior systemic therapy in any setting. Patients may experience toxicity associated with this combination, including adverse reactions of hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria. These adverse reactions may be managed with a combination of concomitant supportive care medications and judicious lenvatinib dose modifications. This article provides context and guidance for the recognition and management of adverse reactions in patients receiving lenvatinib plus pembrolizumab., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear., Methods: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated., Results: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels., Conclusions: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.)., (Copyright © 2021 Massachusetts Medical Society.)