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The intrinsic resistance of BCR-ABL-expressing chronic myeloid leukemia stem cells to treatment with tyrosine-kinase inhibitors requires growth-factor signaling through the proteins c-Fos and DUSP1. Combined inhibition of BCR-ABL, c-Fos, and DUSP1 eradicated leukemia in vivo , pointing to a new therapeutic strategy for kinase-driven leukemias. Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos ) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase–induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth-factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles' heel of kinase-driven cancers.

Seedling age and soil condition after puddling affects stand establishment, growth and productivity of mechanically transplanted rice (MTR). Study was performed to evaluate different puddled soil settling periods (24, 48 and 72 hours) and seedling age (20, 25 and 30 days) for decreasing the missing hills while improving plant and root growth, and consequently grain yield of MTR. Experiment was conducted using randomized complete block design (RCBD) with split-plot arrangement and three replications during 2020 and 2021. Shoot and root length as well as dry mass of rice seedlings sown in trays were significantly increased with increase in seedling age. Increase in puddled soil settling period and seedling age significantly interacted in increasing filled hills and decreasing missing hills after transplanting the nursery. Root length, plant height and root/shoot ratio was significantly higher at 72 hours puddled soil setting period; however, seedling age didn't affect plant growth. The productive tillers, total dry matter (TDM) and grain yield of MTR was improved interactively by 72 hours puddled soil settling period and 25 days old nursery. The 1000-grain weight was increased by increase in puddled soil setting period while didn't affect significantly by seedling age. Benefit cost ratio (BCR) and net returns were substantially improved by 72 hours puddled soil settling period and 25 days seedling age. In conclusion, 72 hours puddled soil settling period and 25 days seedling age improved the yield and economic returns by decreasing missing hills; hence could be employed to enhance yield and economic benefits of MTR.

Wheat productivity could be improved by ridge sowing with optimized seed rate for different varieties. This 3-years study was conducted to determine the optimum seed rate for different varieties of ridge sown wheat for better yield and related components. Wheat varieties (Faisalabad-08, Punjab-11 and Galaxy-13) were sown on ridges using two different seed rates (125 and 150 kg ha-1). Increase in seed rate improved the emergence (plants per m2), number of productive tillers per m2 and grain yield (3-7%) of all wheat varieties although productive tillers per plant, number of grains per spike and 1000-grain weight was decreased. Faislabad-08 performed better regarding grain yield and related components among all varieties. Seed rate and varieties did not interact significantly for studied traits. Correlation analysis revealed that grain yield was positively correlated with number of productive tillers per m2 during all years and grain weight during first year; while, negatively correlated with number of grains per spike during second year indicating that increase in grain yield was associated mainly with increase in number of productive tillers per unit area in response to seed rate. In conclusion, increase in seed rate improved the grain yield of ridge sown wheat by enhancing the number of productive tillers per unit area and could be exploited to improve the wheat productivity.

Climate change has affected optimum sowing time of wheat and yield formation by fluctuation in temperature regimes during sowing season of crop. However, different varieties could differ in their potential for yield formation in response to sowing time. This 3-years study was conducted to ascertain impact of sowing dates on grain yield and critical yield component of different wheat varieties. Wheat varieties (Lasani-08, Faislabad-08, Millat-11, AARI-11 and Punjab-11) were sown on different sowing dates (November 01, November 15, November 30 and December 15). Yield and related traits of all varieties were decreased by delayed sowing. Early sown crop (November 01) had maximum emergence which decreased gradually with delayed sowing. Tillers m-2, grain weight, grains per spike and yield of all varieties was greater on November 15 sowing and decreased by sowing afterwards (November 30 - December 15). Although Lasani-08 and Punjab-11 both were high yielders but grain yield of AARI-11 was least affected by sowing time. Linear regression revealed that sowing time manifested negative relations with emergence and grain weight of wheat varieties indicating them the most affected traits in response to temporal variation in sowing. Sowing time had negative relation with number of tillers for only Lasani-08 and Punjab-11, while non-significant relation with grains per spike. Nonetheless, tillers m-2 and grains per spike were correlated positively with wheat yield indicating them most crucial yield imparting traits. In conclusion, wheat sowing on November 15 produced maximum yield; and number of tillers was critical yield determining component followed by grains number per spike in response to sowing dates.

JM-216 is an orally bioavailable platinum compound with activity against many tumor models. The objective of this study was to determine the safety profile and anti-tumor activity of JM-216 in patients with hormone refractory prostate cancer (HRPC) when given orally daily x 5 days. In this open label phase II study JM-216 was administered orally at the dose of 120 mg/m2/d for 5 days every 4 weeks. Patients continued on the therapy until evidence of disease progression or intolerable toxicity developed. Dose escalation and de-escalation were allowed according to patient's tolerance. Thirty-nine patients were enrolled onto the study and received a total of 155 courses (median 2, range 1-16) of JM-216. Dose delays (77% of courses) and dose reductions (31% of courses) were common and were mainly due to myelosupression. Treatment was discontinued in 5 patients due to treatment related toxicities. One patient developed myelodysplastic syndrome 11 months after the start of treatment. The most frequent grade III or higher adverse events included thrombocytopenia (54%), neutropenia (52%), anemia (24%) nausea (13%), vomiting (16%) and diarrhea (28%). PSA response was assessed in 32 patients, 10 (26%) had partial response, 14 (36%) had stable disease while PSA progression was seen in 8 (21%) patients. Of 20 (54%) patients with measurable disease two patients had a documented partial response. Although JM-216 had moderate activity in HRPC when given on daily basis for 5 days, it is associated with significant treatment related toxicities in this patient population.

Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34 + hematopoietic stem and progenitor cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 10 6 CD34 + cells kg –1 within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12–201.33, P  < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36–549.35, P  < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34 + HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529 The phase 3 GENESIS trial reports the superiority of the novel CXCR4 inhibitor motixafortide with G-CSF in mobilizing hematopoietic progenitor cells for autologous stem cell transplantation in multiple myeloma.

Myelodysplastic syndromes (MDS) traditionally have been grouped together as a disease entity based on clinical phenomena seen in association. Despite the similarities, there is great heterogeneity among the syndromes. Recent insights have shown, however, that there exists a biologically cohesive theme that unifies and thereby validates the conceptual interconnectedness. The first suggestion that such a relationship existed where biology could directly explain the observed cytopenias was the finding of excessive premature apoptosis of hematopoietic cells in MDS marrows. This apoptosis was mediated by paracrine as well as autocrine factors implicating both the seed and the soil in the pathology of the disease. Pro-inflammatory cytokines in the marrow microenvironment were mainly the paracrine mediators of apoptosis, but how the clonal cells committed suicide because of autocrine stimulation had remained a mystery for more than a decade. It has been shown now that deregulation of ribosome biogenesis can initiate a stress response in the cell through the p53 signaling pathway. Congenital anemias had been associated with mutations in ribosomal protein genes. The surprise came with the investigation of 5q- syndrome patients where haplo-insufficiency of the ribosomal protein gene RPS14 was found to be the cause of this MDS subtype. Similar ribosomal deregulation was shown to be present in all varieties of MDS patients, serving as another unifying characteristic. In addition to these findings, there are other DNA-related abnormalities such as uniparental disomy, mutations in the TET2 gene, and epigenetic phenomena that are associated with and occur across all types of MDS. This paper summarizes the themes unifying this heterogeneous group of diseases.

Tyrosine kinase inhibitor (TKI) therapy for human cancers is not curative, with relapse due to the continuing presence of tumor cells, referred to as minimal residual disease (MRD) cells. MRD stem or progenitor cells survival in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here, we report that oncogenic kinase and growth factor signaling converge to induce the expression of the signaling proteins c-Fos and Dusp1. Genetic deletion of c-Fos and Dusp1 suppressed tumor growth in a BCR-ABL-induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-Fos, Dusp1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in primary CML patient xenotransplanted mice. Growth factor signaling also conferred TKI resistance and induced c-FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-Fos and Dusp1 expression levels determine the threshold of TKI efficacy, such that growth factor-induced expression of c-Fos and Dusp1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and may represent a unifying Achilles heel of kinase-driven cancers.