Blast phase of chronic myeloid leukemia presenting as early T-cell precursor acute lymphoblastic leukemia.

OBJECTIVES: The blasts in most cases of chronic myeloid leukemia blast phase (CML-BP) have a myeloid or precursor-B immunophenotype, with only a small subset having T-cell or natural killer-cell lineage. Patients with CML-BP having early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) are extremely rare. METHODS: We report the clinicopathologic, immunophenotypic, and molecular genetic features and outcome of 3 patients with CML-BP who had ETP-ALL, with a review of the literature. RESULTS: Only patient 1 had a history of chronic myeloid leukemia chronic phase. Fluorescence in situ hybridization revealed BCR::ABL1 rearrangement in cells with round nuclei (blasts) and cells with segmented nuclei (neutrophils) in cases 2 and 3, supporting a diagnosis of CML-BP rather than de novo Ph+ ETP-ALL. The blasts were positive for cytoplasmic CD3, CD7, CD33, and CD117; were negative for CD1a and CD8; and had dim CD5 expression in 2 cases. Next-generation sequencing showed a TET2 mutation in case 1 and BCOR, RUNX1, and STAG2 mutations in case 3. All patients received chemotherapy and tyrosine kinase inhibitors. Patients 2 and 3 died 33 days and 39 days, respectively, after diagnosis. Patient 1 received stem cell transplantation and was alive 14 months after blast phase. CONCLUSIONS: Patients with CML-BP may have ETP-ALL. These patients usually have an aggressive clinical course, requiring intensive therapy, and may benefit from stem cell transplantation.

Clinicopathologic features and outcomes of acute leukemia harboring PICALM::MLLT10 fusion.

The PICALM::MLLT10 fusion is a rare but recurrent cytogenetic abnormality in acute leukemia, with limited clinicopathologic and outcome data available. Herein, we analyzed 156 acute leukemia patients with PICALM::MLLT10 fusion, including 12 patients from our institutions and 144 patients from the literature. The PICALM::MLLT10 fusion preferentially manifested in pediatric and young adult patients, with a median age of 24 years. T-lymphoblastic leukemia/lymphoma (T-ALL) constituted 65% of cases, acute myeloid leukemia (AML) 27%, and acute leukemia of ambiguous lineage (ALAL) 8%. About half of T-ALL were classified as an early T-precursor (ETP)-ALL. In our institutions' cohort, mediastinum was the most common extramedullary site of involvement. Eight of 12 patients were diagnosed with T-ALL exhibiting a pro-/pre-T stage phenotype (CD4/CD8-double negative, CD7-positive), and frequent CD79a expression. NGS revealed pathogenic mutations in 5 of 6 tested cases, including NOTCH1, and genes in RAS and JAK-STAT pathways and epigenetic modifiers. Of 138 cases with follow-up, pediatric patients (<18 years) had 5-year overall survival (OS) of 71%, significantly better than adults at 33%. The 5-year OS for AML patients was 25%, notably shorter than T-ALL patients at 54%; this distinction was observed in both pediatric and adult populations. Furthermore, adult but not pediatric ETP-ALL patients demonstrated inferior survival compared to non-ETP-ALL patients. Neither karyotype complexity nor transplant status had a discernible impact on OS. In conclusion, PICALM::MLLT10 fusion is most commonly seen in T-ALL patients, particularly those with an ETP phenotype. AML and adult ETP-ALL patients had adverse prognosis. PICALM::MLTT10 fusion testing should be considered in T-ALL, AML, and ALAL patients.

High-temperature annealing behavior of cold-rolled electrolytic tough-pitch copper.

Pure copper is very soft, however, hardening the pure copper with most strengthening mechanisms leads to a significant reduction in electrical conductivity. Grain refinement is a better strengthening mechanism to maintain high enough electrical conductivity. Plastic deformation at room temperature followed by post-annealing is one of the best methods to achieve fine-grained metals and alloys. In this research, the high-temperature annealing behavior of cold-rolled electrolytic tough-pitch (ETP) copper sheets was studied. 90 % asymmetric cold rolling followed by high-temperature post-annealing at 673 K for 1, 2, 5, 10, 30, 60, and 120 min were applied on the copper. The microstructure was significantly changed with increasing annealing time from 1 to 2 min owing to full recrystallization. With increasing the annealing duration, the grain size is increased. The formation of equiaxed grains with a smaller size (∼9 µm) compared to the full-annealed (initial) sample (∼68 µm) is observed after the longest time of post-annealing (120 min) due to the pinning effect of Cu2O particles. The post-annealed copper sheets processed by asymmetric rolling (in this work) exhibited a more homogeneous microstructure through the thickness compared to the symmetric rolling due to more uniform stored strain energy. The results showed that the first deformed grains that undergo recrystallization during post-annealing are Goss-oriented grains. With an increase in the post-annealing time, the S and Copper components were eliminated and a strong Cube and P texture orientations were formed. Interestingly, after 1 min of post-annealing, the yield and tensile strength enhanced to 410.2 MPa and 418.6 MPa owing to the annealing hardening phenomenon. The hardness and strength reached a constant value after the post-annealing for 10 min and above. With increasing the post-annealing duration, the central area of fracture surfaces (consisting of ductile dimples) became larger and the outer region (consisting of flat surfaces and shear dimples) became smaller, showing a shift towards perfect ductile fracture. With the increase of post-annealing time from 1 min to 120 min, the electrical conductivity was increased from 77.6 to 97.5 %IACS. The presence of the Cube texture increased the electron mobility compared to the P orientation, by reducing the mean distance that they can travel without scatter. From the obtained results, it can be concluded that the asymmetric cold rolling followed by high-temperature post-annealing is capable of strength improvement and maintaining electrical conductivity in copper.

Vulnerability of Eastern Tropical Pacific chondrichthyan fish to climate change.

Climate change is an environmental emergency threatening species and ecosystems globally. Oceans have absorbed about 90% of anthropogenic heat and 20%-30% of the carbon emissions, resulting in ocean warming, acidification, deoxygenation, changes in ocean stratification and nutrient availability, and more severe extreme events. Given predictions of further changes, there is a critical need to understand how marine species will be affected. Here, we used an integrated risk assessment framework to evaluate the vulnerability of 132 chondrichthyans in the Eastern Tropical Pacific (ETP) to the impacts of climate change. Taking a precautionary view, we found that almost a quarter (23%) of the ETP chondrichthyan species evaluated were highly vulnerable to climate change, and much of the rest (76%) were moderately vulnerable. Most of the highly vulnerable species are batoids (77%), and a large proportion (90%) are coastal or pelagic species that use coastal habitats as nurseries. Six species of batoids were highly vulnerable in all three components of the assessment (exposure, sensitivity and adaptive capacity). This assessment indicates that coastal species, particularly those relying on inshore nursery areas are the most vulnerable to climate change. Ocean warming, in combination with acidification and potential deoxygenation, will likely have widespread effects on ETP chondrichthyan species, but coastal species may also contend with changes in freshwater inputs, salinity, and sea level rise. This climate-related vulnerability is compounded by other anthropogenic factors, such as overfishing and habitat degradation already occurring in the region. Mitigating the impacts of climate change on ETP chondrichthyans involves a range of approaches that include addressing habitat degradation, sustainability of exploitation, and species-specific actions may be required for species at higher risk. The assessment also highlighted the need to further understand climate change's impacts on key ETP habitats and processes and identified knowledge gaps on ETP chondrichthyan species.

El cambio climático es una emergencia medioambiental que amenaza a especies y ecosistemas en todo el mundo. Los océanos han absorbido alrededor del 90% del calor antropogénico y entre el 20% y el 30% de las emisiones de carbono, lo que ha provocado su calentamiento, acidificación, desoxigenación, cambios en la estratificación de los océanos y en la disponibilidad de nutrientes, así como fenómenos extremos más pronunciados. Dadas las predicciones de cambios, hay una importante necesidad de entender cómo las especies marinas se verán afectadas. En este estudio utilizamos una Evaluación Integrada de Riesgos para evaluar la vulnerabilidad de 132 condrictios del Pacífico Tropical Oriental (PTO) a los impactos del cambio climático. Adoptando un enfoque preventivo, estimamos que la vulnerabilidad general al cambio climático es Alta para casi una cuarta parte (23%) de las especies de condrictios del PTO evaluadas y Moderada para gran parte del resto (76%). La mayoría de las especies altamente vulnerables son batoideos (77%), y una gran proporción de éstas (90%) son especies costeras o especies pelágicas que utilizan los hábitats costeros como áreas de crianza. Seis especies de batoideos tuvieron una vulnerabilidad Alta en los tres componentes de la evaluación. Esta evaluación indica que las especies costeras, en particular las que dependen de áreas de crianza costeras, son las más vulnerables al cambio climático. Es probable que el calentamiento de los océanos, junto con la acidificación y la posible desoxigenación, tenga efectos generalizados sobre las especies de condrictios del PTO, pero las especies costeras se verán también afectadas por los cambios en los aportes de agua dulce, la salinidad y el aumento del nivel del mar. Esta vulnerabilidad relacionada con el clima se ve agravada por otros factores antropogénicos que ya se están produciendo en la región, como la sobrepesca y la degradación del hábitat. La mitigación de los impactos del cambio climático sobre los condrictios del PTO implica medidas que incluyan abordar la degradación del hábitat y la sostenibilidad de la explotación pesquera, y acciones para las especies de mayor riesgo son necesarias. Esta evaluación también destaca la necesidad de comprender mejor los impactos del cambio climático en los hábitats y procesos clave del PTO y las lagunas de conocimiento identificadas en relación con las especies de condrictios del PTO.

Immunophenotypic but Not Genetic Changes Reclassify the Majority of Relapsed/Refractory Pediatric Cases of Early T-Cell Precursor Acute Lymphoblastic Leukemia.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) develops from very early cells with the potential for both T-cell and myeloid differentiation. The ambiguous nature of leukemic blasts in ETP-ALL may lead to immunophenotypic alterations at relapse. Here, we address immunophenotypic alterations and related classification issues, as well as genetic features of relapsed pediatric ETP-ALL. Between 2017 and 2022, 7518 patients were diagnosed with acute leukemia (AL). In addition to conventional immunophenotyping, karyotyping, and FISH studies, we performed next-generation sequencing of the T-cell receptor clonal repertoire and reverse transcription PCR and RNA sequencing for patients with ETP-ALL at both initial diagnosis and relapse. Among a total of 534 patients diagnosed with T-cell ALL (7.1%), 60 had ETP-ALL (11.2%). Ten patients with ETP-ALL experienced relapse or progression on therapy (16.7%), with a median time to event of 5 months (ranging from two weeks to 5 years). Most relapses were classified as AL of ambiguous lineage (n = 5) and acute myeloid leukemia (AML) (n = 4). Major genetic markers of leukemic cells remained unchanged at relapse. Of the patients with relapse, four had polyclonal leukemic populations and a relapse with AML or bilineal mixed-phenotype AL (MPAL). Three patients had clonal TRD rearrangements and relapse with AML, undifferentiated AL, or retention of the ETP-ALL phenotype. ETP-ALL relapse requires careful clinical and laboratory diagnosis. Treatment decisions should rely mainly on initial examination data, taking into account both immunophenotypic and molecular/genetic characteristics.

Synergistic Effect of Venetoclax and Bendamustine in Early T-cell Precursor Acute Lymphoblastic Leukemia.

BACKGROUND/AIM: To date, therapeutic options for T-cell acute lymphoblastic leukemia (T-ALL) remain very limited. This study evaluated the efficacy of monotherapies and combination therapies including a selective BCL-2 inhibitor for T-ALL cell lines, namely Jurkat, CCRF-CEM, and Loucy. MATERIALS AND METHODS: Loucy is an early T-precursor ALL (ETP-ALL) cell line characterized by an immature phenotype, whereas Jurkat and CCRF-CEM are late T-cell progenitor ALL (LTP-ALL) cell lines. Monotherapy was conducted with venetoclax, cytarabine, bendamustine, or azacytidine, whereas combination therapy was performed with venetoclax plus cytarabine, venetoclax plus bendamustine, or venetoclax plus azacytidine. Cell viability assay was conducted after 48 h using Trypan blue and the 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). Statistical analysis for evaluating synergistic interactions between anticancer drugs was performed by using the SynergyFinder Plus and drc R package. RESULTS: Adding venetoclax to cytarabine, bendamustine, or azacitidine achieved an additive effect, with Loewe synergic scores ranging from -10 to 10 in Jurkat and CCRF-CEM. Conversely, the combination of venetoclax and cytarabine displayed an additive effect (Loewe synergic score: 8.45 and 5.82 with MTS and Trypan blue assays, respectively), whereas venetoclax plus bendamustine or azacitidine exhibited a synergistic effect (Loewe synergic score >10 with MTS assay) in Loucy. Remarkably, the Bliss/Loewe score revealed that the combination of venetoclax and bendamustine was the most synergistic, yielding a score of 13.832±0.55. CONCLUSION: The combination of venetoclax and bendamustine demonstrated the greatest synergistic effect in suppressing ETP-ALL cell proliferation. Further studies are warranted to determine the mechanisms for the synergism between venetoclax and bendamustine in high-risk T-ALL.

Probabilistic Tractography-Based Tremor Network Connectivity in Tremor Dominant Parkinson's Disease and Essential Tremor plus.

Background: The basal ganglia-thalamocortical (BGTC) and cerebello-thalamocortical (CTC) networks are implicated in tremor genesis; however, exact contributions across disorders have not been studied. Objective: Evaluate the structural connectivity of BGTC and CTC in tremor-dominant Parkinson's disease (TDPD) and essential tremor plus (ETP) with the aid of probabilistic tractography and graph theory analysis. Methods: Structural connectomes of the BGTC and CTC were generated by probabilistic tractography for TDPD (n = 25), ETP (ET with rest tremor, n = 25), and healthy control (HC, n = 22). The Brain Connectivity Toolbox was used for computing standard topological graph measures of segregation, integration, and centrality. Tremor severity was ascertained using the Fahn-Tolosa-Marin tremor rating scale (FTMRS). Results: There was no difference in total FTMRS scores. Compared with HC, TDPD had a lower global efficiency and characteristic path length. Abnormality in segregation, integration, and centrality of bilateral putamen, globus pallidus externa (GPe), and GP interna (GPi), with reduction of centrality of right caudate and cerebellar lobule 8, was observed. ETP showed reduction in segregation and integration of right GPe and GPi, ventrolateral posterior nucleus, and centrality of right putamen, compared with HC. Differences between TDPD and ETP were a reduction of strength of the right putamen, and lower clustering coefficient, local efficiency, and strength of the left GPi in TDPD. Conclusions: Contrary to expectations, TDPD and ETP may not be significantly different with regard to tremor pathogenesis, with definite overlaps. There may be fundamental similarities in network disruption across different tremor disorders with the same tremor activation patterns, along with disease-specific changes.

Efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation treatment for adolescent and adult Tlymphoblastic leukemia /lymphoma: a large cohort multicenter study in China.

T lymphoblastic leukemia /lymphoma (T-ALL/LBL) is a rare and highly aggressive neoplasm of lymphoblasts. We evaluated 195 T-ALL/LBL adolescent and adult patients who received ALL-type chemotherapy alone (chemo,n = 72) or in combination with autologous hematopoietic stem cell transplantation(auto-HSCT,n = 23) or allogeneic hematopoietic stem cell transplantation(allo-HSCT,n = 100) from January 2006 to September 2020 in three Chinese medical centers. 167 (85.6%) patients achieved overall response (ORR) with 138 complete response (CR) patients (70.8%) and 29 partial response (PR) patients (14.8%). Until October 1, 2023, no difference was found in 5-year overall survival (5-OS) and 5-year progression free survival(5-PFS) between allo-HSCT and auto-HSCT (5-OS 57.9% vs. 36.7%, P = 0.139, 5-year PFS 49.4% vs. 28.6%, P = 0.078) for patients who achieved CR, for patients who achieved PR, allo-HSCT recipients had higher 5-OS compared with chemo alone recipients (5-OS 23.8% vs. 0, P = 0.042). For patients undergoing allo-HSCT, minimal residual disease (MRD) negative population showed better 5-OS survival compared with MRD positive patients (67.8% vs. 19.6%, p = 0.000). There were no significant differences between early T-cell precursor (ETP), NON-ETP patients with or without expression of one or more myeloid-associated or stem cell-associated (M/S+) markers (NON-ETP with M/S+, NON-ETP without M/S+) groups in allo-HSCT population for 5-OS. (62.9% vs. 54.5% vs.48.4%, P > 0.05). Notch mutations were more common in patients with non-relapsed/refractory disease than relapsed/refractory disease (χ² =4.293, P = 0.038). In conclusion, Allo-HSCT could be an effective consolidation therapy not just for patients with CR, but also for those who achieved PR. The prognosis is significantly improved by obtaining MRD negative prior to allogeneic transplantation.

CD133 ligand-enhanced etoposide-liposome complex for targeted killing of lung cancer cells.

Lung cancer has a high incidence rate and a low cure rate, hence the urgent need for effective treatment methods. Current lung cancer drugs have several drawbacks, including low specificity, poor targeting, drug resistance, and irreversible damage to normal tissues. Therefore, there is a need to develop a safe and effective new drug that can target and kill tumor cells. In this study, we combined nanotechnology and biotechnology to develop a CD133 ligand-modified etoposide-liposome complex (Lipo@ETP-CD133) for targeted therapy of lung cancer. The CD133 ligand targeted lung cancer stem cells, causing the composite material to aggregate at the tumor site, where high levels of ETP liposomes could exert a strong tumor-killing effect. Our research results demonstrated that this nano-drug had efficient targeting and tumor-killing effects, indicating its potential for clinical application.

Differential patterns of functional connectivity in tremor dominant Parkinson's disease and essential tremor plus.

Tremor dominant Parkinson's disease (TDPD) and essential tremor plus (ETP) syndrome are commonly encountered tremor dominant neurological disorders. Although the basal ganglia thalamocortical (BGTC) and cerebello thalamocortical (CTC) networks are implicated in tremorogenesis, the extent of functional connectivity alterations across disorders is uncertain. This study aims to evaluate functional connectivity of the BGTC and CTC in TDPD and ETP. Resting state functional MRI was acquired for 25 patients with TDPD, ETP and 22 healthy controls (HC). Following pre-processing and denoising, seed-to-voxel based connectivity was carried out at FDR < 0.05 using ROIs belonging to the BGTC and CTC. Fahn-Tolosa-Marin tremor rating scale (FTMRS) was correlated with the average connectivity values at FDR < 0.05. Compared to HC, TDPD showed decreased connectivity between cerebellum and pre, post central gyrus. While, ETP showed decreased connectivity between pallidum and occipital cortex, precuneus, cuneus compared to HC. In comparison to ETP, TDPD showed increased connectivity between precentral gyrus, pallidum, SNc with the default mode network (DMN), and decreased connectivity between cerebellum with superior, middle frontal gyrus was observed. Tremor severity positively correlated with connectivity between SNc and DMN in TDPD, and negatively correlated with pallidal connectivity in ETP. Pattern of BGTC, CTC involvement is differential i.e., higher connectivity of the BGTC nodes in TDPD, and higher connectivity of cerebellar nodes in ETP. The interesting observation of pallidal involvement in ETP suggests the role of BGTC in the pathogenesis of ETP, and indicated similarities in concepts of tremor genesis in TDPD and ETP.

Selective and ultrafast oxidation of multiple pollutants by biomorphic diatomite-based catalyst and stable catalytic Fenton-like membrane: Degradation behavior and mechanism analysis.

Carbon-driven advanced oxidations show great potential in water purification, but regulating structures and properties of carbon-based catalysts to achieve ultrafast Fenton-like reactions remains challenging. Herein, a biomorphic diatomite-based catalyst (BD-C) with Si-O doping was prepared using natural diatomite as silicon source and porous template. The results showed that the metal-free BD-C catalyst exhibited ultrafast oxidation performances (0.95-2.58 min-1) towards a variety of pollutants in PMS-based Fenton-like reaction, with the Fenton-like activity of metal-free catalyst comparable to metal-based catalysts or even single-atom catalysts. Pollutants (e.g., CP, BPA, TC, and PCM) with electron-donating groups exhibited extremely low PMS decomposition with overwhelmed electron transfer process (ETP), while high PMS consumption was induced by the addition of electron-withdrawing pollutants (e.g., MNZ and ATZ), which was dominated by radical oxidation. The BD-C/PMS system also showed a high ability to resist the environmental interference. In-depth theoretical investigations demonstrated that the coordination of Si-O can lower the potential barrier of PMS activation for accelerating the generation of radicals, and also promote the electron transfer from pollutants to the BD-C/PMS complexes. In addition, BD-C was deposited onto a polytetrafluoroethylene membrane (PTFEM) with 100% of pollutants removal over 10 h, thereby revealing the promising prospects of utilizing BD-C for practical applications.

Decoding the genetic symphony: Profiling protein-coding and long noncoding RNA expression in T-acute lymphoblastic leukemia for clinical insights.

T-acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy characterized by the abnormal proliferation of immature T-cell precursors. Despite advances in immunophenotypic classification, understanding the molecular landscape and its impact on patient prognosis remains challenging. In this study, we conducted comprehensive RNA sequencing in a cohort of 35 patients with T-ALL to unravel the intricate transcriptomic profile. Subsequently, we validated the prognostic relevance of 23 targets, encompassing (i) protein-coding genes-BAALC, HHEX, MEF2C, FAT1, LYL1, LMO2, LYN, and TAL1; (ii) epigenetic modifiers-DOT1L, EP300, EML4, RAG1, EZH2, and KDM6A; and (iii) long noncoding RNAs (lncRNAs)-XIST, PCAT18, PCAT14, LINC00202, LINC00461, LINC00648, ST20, MEF2C-AS1, and MALAT1 in an independent cohort of 99 patients with T-ALL. Principal component analysis revealed distinct clusters aligning with immunophenotypic subtypes, providing insights into the molecular heterogeneity of T-ALL. The identified signature genes exhibited associations with clinicopathologic features. Survival analysis uncovered several independent predictors of patient outcomes. Higher expression of MEF2C, BAALC, HHEX, and LYL1 genes emerged as robust indicators of poor overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS). Higher LMO2 expression was correlated with adverse EFS and RFS outcomes. Intriguingly, increased expression of lncRNA ST20 coupled with RAG1 demonstrated a favorable prognostic impact on OS, EFS, and RFS. Conclusively, several hitherto unreported associations of gene expression patterns with clinicopathologic features and prognosis were identified, which may help understand T-ALL's molecular pathogenesis and provide prognostic markers.

Evaluation of sleep and therapeutic education needs of military with PTSD.

Sleep disorders in post-traumatic stress disorder (PTSD) are both diagnostic (nocturnal reliving) and prognostic. Poor sleep worsens the daytime symptomatology of PTSD and makes it resistant to treatment. However, no specific treatment is codified in France to treat these sleep disorders although sleep therapies (cognitive behavioural therapy for insomnia, psychoeducation and relaxation) have proven for years to be effective in treating insomnia. Therapeutic sessions can be part of a therapeutic patient education program, which is a model for the management of chronic pathologies. It allows for an improvement in a patient's quality of life and enhanced medication compliance. We therefore carried out an inventory of sleep disorders of patients with PTSD. First, we collected data by means of sleep diaries concerning the population's sleep disorders at home. Then we assessed the population's expectations and needs regarding its management of sleep, thanks to a semi-qualitative interview. The data from sleep diaries, which was consistent with the literature, showed that our patients suffered from severe sleep disorders that strongly impact their daily lives, with 87% of patients having an increased sleep onset latency, and 88% having nightmares. We observed a strong demand from patients for specific support for these symptoms, 91% expressing an interest in a TPE program targeting sleep disorders. Thanks to the data collected, the emerging themes for a future therapeutic patient education program targeting sleep disorders of soldiers with PTSD are: sleep hygiene; management of nocturnal awakenings, including nightmares; and psychotropic drugs.

A Comparative Analysis of Early T-Cell Precursor Lymphoblastic Leukemia/Lymphoma (ETP-ALL/LBL) and Non-ETP-ALL/LBL in a Tertiary Cancer Care Center Based in Western India.

Early T-cell precursor lymphoblastic leukemia (ETP-ALL) has a unique immunophenotype with very early T-cell differentiation. The current study summarises the distinct clinicopathological aspects of ETP-ALL and compares them with non-ETP-ALL. Twenty-nine ETP-ALL and 191 non-ETP-ALL cases were retrieved between 2018 and 2021. A P value was determined for each of the patient charaterisics (Table 1) to see for any significant relationship (P < 0.05) with ETP-ALL versus non-ETP-ALL. Kaplan-Meier log rank test was applied to look for any significant differences in OS for both the ALLs. ETP-ALL had an incidence of 12.6% out of total T-Acute lymphoblastic leukemia (T-ALL/LBL) in the past 3-years. Compared to non-ETP-ALL, ETP-ALL cases were associated with lower median age and male-to-female ratio. There was no statistically significant difference in the complete remission rate between both the subtypes. ETP-ALL was seen to be associated with high induction failure and relapse rate compared to non-ETP-ALL. To summarise, since the 2-year OS was poor compared to western research (for both ALLs), an intensive chemo-regimen should be implemented in the current situation. Some unusual markers were observed on flow-cytometry (ETP-ALL), which can be useful for MRD quantification, prognosis, and further trials for newer targeted therapies.

Mechanism of anticancer effect of ETP-45658, a PI3K/AKT/mTOR pathway inhibitor on HT-29 Cells.

The PI3K pathway plays a crucial role in tumor cell proliferation across various cancers, including colon cancer, making it a promising treatment target. This study aims to investigate the antiproliferative activity of ETP-45658, a PI3K/AKT/mTOR pathway inhibitor, on colon cancer and elucidate the underlying mechanisms. HT-29 colon cancer cells were treated with varying doses of ETP 45658 and its cytotoxic effect assessed using the XTT cell viability assay.ELISA was also used to measure TAS, TOS, Bax, BCL-2, cleaved caspase 3, cleaved PARP, and 8-oxo-dG levels. Flow cytometry was performed to investigate apoptosis, cell cycle, caspase 3/7 activity, and mitochondrial membrane potential. Additionally, following the administration of DAPI (4,6-diamidino-2-phenylindole) dye, the cells were visualized using an immunofluorescence microscope. It was observed that ETP-45658 exerted a dose-dependent and statistically significant antiproliferative effect on HT-29 colon cancer cells. Further investigations using the IC50 dose showed that ETP-45658 decreased TAS levels and increased TOS levels and revealed that it upregulated apoptotic proteins while downregulating anti-apoptotic proteins. Our findings also showed that it increased Annexin V binding, arrested the cell cycle at G0/G1 phase, induced caspase 3/7 activity, impaired mitochondrial membrane potential, and ultimately triggered apoptosis in HT-29 cells. ETP-45658 shows promise against colon cancer by inducing cell death, and oxidative stress, and arresting the cell cycle. Targeting the PI3K/AKT/mTOR pathway with ETP-45658 offers exciting potential for colon cancer treatment.

Implementation of water hyacinth (Eichhornia crassipes) and water lettuce (Pistia stratiotes) in the re-treatment of conventionally treated pharmaceutical wastewater: a case study of Radiant Pharmaceuticals Limited, Dhaka, Bangladesh.

Since Bangladesh already has robust pharmaceutical industries, nearly all companies owned effluent treatment plant (ETP) facilities to improve the quality of wastewater. Water retreatment utilizing affordable, accessible, and environmentally sustainable techniques have not yet been thoroughly investigated. In this study, the potential of water hyacinth and water lettuce was investigated at three different concentrations: 50% of total volume coverages (1000 g macrophytes/2000 ml water), 75% of total volume coverages (1500 g macrophytes/2000 ml water), and 100% of total volume coverages (2000 g macrophytes/2000 ml water) on the post-treated ETP's wastewater for 3 weeks in a mesocosm environment. Heavy metals, such as chromium (Cr) and nickel (Ni) along with physicochemical parameters (pH, EC, TDS, DO, and BOD5) were measured after 7 days intervals. Results indicated that water hyacinth was considerably more efficient than water lettuce at removing many factors, including metals. Water hyacinth was able to remove 79.15% of nickel and 92.97% of chromium while also increasing DO and EC by 36.72% and 14.59%, respectively, at 100% of total volume coverages. On the other hand, 100% of the total volume coverage of water lettuce decreased the pH, TDS, and BOD5 readings by 6.70%, 31.62%, and 87.61%, respectively. With each treatment, the water quality significantly improved over the control. The findings suggest that the pharmaceutical industries may improve the quality of their treated wastewater even more by integrating phytoremediation technology with traditional ETP facilities.

Evaluation of circulating insulin-like growth factor-1, heart-type fatty acid-binding protein, and endotrophin levels as prognostic markers of COVID-19 infection severity.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a worldwide pandemic challenge spreading enormously within a few months. COVID-19 is characterized by the over-activation of the immune system causing cytokine storm. Insulin-like growth factor-1 (IGF-1) pathway can regulate the immune response via interaction with various implicated cytokines. Heart-type fatty acid-binding protein (H-FABP) has been shown to promote inflammation. Given the fact that coronavirus infections induce cytokines secretion leading to inflammatory lung injury, it has been suggested that H-FABP levels are affected by COVID-19 severity. Moreover, endotrophin (ETP), the cleavage product of collagen VI, may be an indicator of an overactive repair process and fibrosis, considering that viral infection may predispose or exacerbate existing respiratory conditions, including pulmonary fibrosis. This study aims to assess the prognostic capacity of circulating IGF-1, HFABP, and ETP, levels for COVID-19 severity progression in Egyptian patients. METHODS: The study cohort included 107 viral RNA-positive patients and an equivalent number of control individuals with no clinical signs of infection. Clinical assessments included profiling of CBC; serum iron; liver and kidney functions; inflammatory markers. Circulating levels of IGF-1; H-FABP, and ETP were estimated using the corresponding ELISA kits. RESULTS: No statistical difference in the body mass index was detected between the healthy and control groups, while the mean age of infected patients was significantly higher (P = 0.0162) than the control. Patients generally showed elevated levels of inflammatory markers including CRP and ESR concomitant with elevated serum ferritin; D dimer and procalcitonin levels, besides the COVID-19 characteristic lymphopenia and hypoxemia were also frequent. Logistic regression analysis revealed that oxygen saturation; serum IGF-1, and H-FABP can significantly predict the infection progression (P < 0.001 each). Both serum IGF-1 and H-FABP as well as O2 saturation showed remarkable prognostic potentials in terms of large AUC values, high sensitivity/specificity values, and wide confidence interval. The calculated threshold for severity prognosis was 25.5 ng/mL; 19.5 ng/mL, 94.5, % and for IGF-1, H-FABP, and O2 saturation; respectively. The calculated thresholds of serum IGF-1; H-FABP, and O2 saturation showed positive and negative value ranges of 79-91% and 72-97%; respectively, with 66-95%, 83-94% sensitivity, and specificity; respectively. CONCLUSION: The calculated cut-off values of serum IGF-1 and H-FABP represent a promising non-invasive prognostic tool that would facilitate the risk stratification in COVID-19 patients, and control the morbidity/mortality associated with progressive infection.

Modification of the Railway Traction Elements.

This paper presents the results of research on a newly developed surface layer made by laser remelting the working surface of the Cu-ETP (CW004A, Electrolytic Tough Pitch) copper section insulator guide with Cr-Al powder. For the investigation, a fibre laser was used with relatively high power, reaching 4 kW, so as to ensure a high gradient of cooling rate for microstructure refinement. The microstructure of the transverse fracture of the layer (SEM) and the distribution of elements in the microareas (EDS) were investigated. The test results showed that chromium does not dissolve in the Cu matrix, and its precipitates take the shape of dendrites. The hardness and thickness of the surface layers as well as the friction coefficient and the influence of the Cr-Al powder feeding speed on them were examined. For the distance from the surface to 0.45 mm, the hardness of the produced coatings is above 100 HV0.3, while the friction coefficient of the produced coatings is in the range of 0.6-0.95. More sophisticated investigation results concern the d-spacing lattice parameters of the crystallographic structure of the obtained Cu phase reaching the range between 3.613-3.624 Å.

Identification of inflamed-phenotype of small cell lung cancer leading to the efficacy of anti-PD-L1 antibody and chemotherapy.

BACKGROUND: Platinum etoposide plus anti-programmed cell death ligand-1 (PD-L1) antibody therapy is the standard of care for extensive-stage small cell lung cancer (ES-SCLC). However, patient characteristics associated with the efficacy of the combination therapy in SCLC are unclear. METHODS: We retrospectively reviewed post-surgical limited-stage (LS)-SCLC and ES-SCLC patients treated with atezolizumab plus carboplatin and etoposide (ACE). The association between SCLC subtypes based on transcriptomic data and pathological findings, including CD8-positive tumor-infiltrating lymphocyte (TIL) status, was investigated in the LS-SCLC cohort. The association between the efficacy of ACE therapy, pathological subtypes, and TIL status was evaluated in the ES-SCLC cohort. RESULTS: The LS-SCLC cohort (N = 48) was classified into four SCLC subtypes (ASCL1 + NEUROD1 [SCLC-A + N, N = 17], POU2F3 [SCLC-P, N = 15], YAP1 [SCLC-Y, N = 10], and inflamed [SCLC-I, N = 6]) based on transcriptomic data. SCLC-I showed enriched immune-related pathways, the highest immune score (CD8A expression and T-cell-inflamed gene expression profiles), and epithelial-mesenchymal transition (EMT), in transcriptional subtypes. Immunohistochemical staining (IHC) showed that SCLC-I had the highest density of CD8-positive TILs in transcriptional subtypes. In the ES-SCLC cohort, the efficacy of ACE therapy did not differ according to pathological subtypes. The progression-free survival (PFS) of TILHigh patients was significantly longer than that of TILLow patients (PFS: 7.3 months vs. 4.0 months, p < 0.001). CONCLUSION: Tumors with a high density of TILs, which represent the most immunogenic SCLC subtype (SCLC-I), based on transcriptomic data could benefit from ACE therapy.

Comparison of flowcytometry-based scoring system for the diagnosis of early T precursor-acute lymphoblastic leukemia.

BACKGROUND: Early T cell precursor-acute lymphoblastic leukemia (ETP-ALL) is a hematolymphoid malignancy where the blasts demonstrate T cell differentiation markers along with stem cell and myeloid antigen expression. The differential diagnosis of ETP-ALL from non-ETP ALL and mixed phenotype acute leukemia is often challenging due to its overlapping immunophenotypic picture with co-expression of myeloid antigens. In this study, we endeavored to describe the immune-phenotype profile of ETP-ALL in our patients and compared the utility of four different scoring systems for better discrimination of these entities. METHODS: This retrospective analysis included 31 ETP-ALL out of 860 acute leukemia cases consecutively diagnosed at the two tertiary care centers. Flowcytometry-based immunophenotype was reviewed for all the cases, and the utility of four flow-based objective scorings was assessed for the diagnosis of ETP-ALL. Receiver operating curves were drawn to compare the different flow-based scoring systems. RESULTS: The prevalence of ETP-ALL was 40% (n = 31/77 T-ALL) in our study group, comprised mainly of adults with a median age of 20 years. The five-marker scoring system had the maximum area under the curve, followed by the seven-marker scoring system. A cut-off of ≥2.5 was more specific (sensitivity: 91%; specificity: 100%), while a score of ≥1.5 was more sensitive but slightly less specific (sensitivity: 94%, specificity: 96%). CONCLUSION: The WHO criteria for the diagnosis of ETP-ALL should be followed across all laboratories to avoid confusion and for better treatment stratification. Flow-based scoring systems can be objectively employed for better detection of cases.