Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the presence of BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab (RTX), an anti-CD20 monoclonal antibody (mAb) is administered in adult BCP-ALL patients with ≥20% of CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of RTX in combination with TKIs. Consequently, we examined the influence of TKIs on the antitumor effectiveness of anti-CD20 mAbs by evaluating CD20 surface levels and conducting in vitro functional assays. All tested TKIs were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of RTX-mediated complement-dependent cytotoxicity. Interestingly, these TKIs displayed varied effects on NK cell-mediated antibody-dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-mAb-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity within patients' blood, determined by ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKIs for combination therapy with anti-CD20 mAbs.

Advancements in cancer immunotherapies targeting CD20: from pioneering monoclonal antibodies to chimeric antigen receptor-modified T cells.

CD20 located predominantly on the B cells plays a crucial role in their development, differentiation, and activation, and serves as a key therapeutic target for the treatment of B-cell malignancies. The breakthrough of monoclonal antibodies directed against CD20, notably exemplified by rituximab, revolutionized the prognosis of B-cell malignancies. Rituximab, approved across various hematological malignancies, marked a paradigm shift in cancer treatment. In the current landscape, immunotherapies targeting CD20 continue to evolve rapidly. Beyond traditional mAbs, advancements include antibody-drug conjugates (ADCs), bispecific antibodies (BsAbs), and chimeric antigen receptor-modified (CAR) T cells. ADCs combine the precision of antibodies with the cytotoxic potential of drugs, presenting a promising avenue for enhanced therapeutic efficacy. BsAbs, particularly CD20xCD3 constructs, redirect cytotoxic T cells to eliminate cancer cells, thereby enhancing both precision and potency in their therapeutic action. CAR-T cells stand as a promising strategy for combatting hematological malignancies, representing one of the truly personalized therapeutic interventions. Many new therapies are currently being evaluated in clinical trials. This review serves as a comprehensive summary of CD20-targeted therapies, highlighting the progress and challenges that persist. Despite significant advancements, adverse events associated with these therapies and the development of resistance remain critical issues. Understanding and mitigating these challenges is paramount for the continued success of CD20-targeted immunotherapies.

Concomitant inhibition of the thioredoxin system and nonhomologous DNA repair potently sensitizes Philadelphia-positive lymphoid leukemia to tyrosine kinase inhibitors.

Breakpoint cluster region-Abelson (BCR::ABL1) gene fusion is an essential oncogene in both chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL). While tyrosine kinase inhibitors (TKIs) are effective in up to 95% of CML patients, 50% of Ph+ B-ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph+ B-ALL. Previous studies have shown that inhibitors of the thioredoxin (TXN) system exert antileukemic activity against B-ALL cells, particularly in combination with other drugs. Here, we present that peroxiredoxin-1 (PRDX1), one of the enzymes of the TXN system, is upregulated in Ph+ lymphoid as compared to Ph+ myeloid cells. PRDX1 knockout negatively affects the viability of Ph+ B-ALL cells and sensitizes them to TKIs. Analysis of global gene expression changes in imatinib-treated, PRDX1-deficient cells revealed that the nonhomologous end-joining (NHEJ) DNA repair is a novel vulnerability of Ph+ B-ALL cells. Accordingly, PRDX1-deficient Ph+ B-ALL cells were susceptible to NHEJ inhibitors. Finally, we demonstrated the potent efficacy of a novel combination of TKIs, TXN inhibitors, and NHEJ inhibitors against Ph+ B-ALL cell lines and primary cells, which can be further investigated as a potential therapeutic approach for the treatment of Ph+ B-ALL.

Gas embolism as a potential cause of death by helium poisoning - Postmortem computed tomography changes in two cases of suicidal helium inhalation.

Evaluation of two suicidal helium inhalation cases is presented, comprising both conventional autopsy methods and postmortem computed tomography. Conventional postmortem examinations reveal no characteristic changes. Modern diagnostic techniques enabled to disclosethe presence of a very large amount of accumulated gas in all examined areas, including veins and arteries of the head, torso, lower extremities, heart chambers, and between muscle fibers in both cases. The changes due to possible putrefaction were taken into consideration - radiological alteration index was calculated. In forensic literature, the reported mechanism of death in helium poisoning is rapid asphyxiation due to oxygen deprivation. However, papers on clinical cases and animal studies with the use of helium report development of gas in body cavities and lethal gas embolism, comprehensible when we take into account the specific physical properties of helium: high permeability and very low solubility in blood. The results reported by the authors are consistent with massive gas embolism similar to changes presentedin cases of decompression illness. They suggest this as the cause of death in helium inhalation cases. Undoubtedly, this requiresconfirmation in further observations, taking into account differentiating diagnosis of air embolism versus oxygen deprivation.

Expectations towards forensic professionals conducting external examinations of dead bodies on the crime scene--results of a questionnaire distributed among public prosecutors in the Mazovian Voivodeship / Oczekiwania wobec uczestnictwa medyków sadowych w ogledzinach zwlok na miejscu ich ujawnienia--wyniki ankiety przeprowadzonej wsród prokuratorów w województwie mazowieckim.

UNLABELLED: The purpose of this study was to determine expectations of public prosecutors towards forensic professionals participating in external examinations of dead bodies performed at the site of finding the corpses. The presence of forensic physicians on the crime scene was recognized as advantageous by all prosecutors; however, expectations associated with corpse inspection did not correspond to capabilities of modern medicine or necessitated repeating activities performed during autopsies. Homicides (99%), deaths of children (86%) and "media" deaths (73%) were indicated as cases when the presence of forensic professional was especially important. Definition of injuries with indication of the causative object made by forensic physicians on the crime scene was the advantage most often chosen by respondents (82%). Almost one third of respondents expected forensic physicians to evaluate the length and direction of wound tracts, more than half of them--to provide a detailed description of injuries, one fifth wanted physicians to determine the exact time of death. Description of post mortem changes was not indicated as the most important benefit by any prosecutor. CONCLUSIONS: Public prosecutors recognized the presence of forensic professionals on the crime scene as advantageous, but their expectations associated with dead body examinations did not correspond to capabilities of forensic medicine or forced physicians to perform activities normally made during autopsy. An algorithm of dead body examination on the crime scene including aims and advantages of such a examination should be developed jointly by prosecutors and forensic medicine specialists.

[The effect of alcohol consumption on the severity of injuries, prognosis and mortality--a review of literature]. / Wplyw spozycia alkoholu etylowego na ciezkosc doznanych obrazen, rokowanie i smiertelnosc--przeglad pismiennictwa.

The paper is a review of the most current academic literature published in the English language and addressing the effect of alcohol consumption on the severity of injuries, prognosis and mortality with special emphasis placed on the consultative usefulness of such publications. The report was inspired by repeated questions asked in association with expert opinions on the effects of injuries and addressing a possible effect of alcohol consumption by the victims on the severity of injuries and prognosis. In case of such questions, a valuable supplement to an opinion based on on the expert's professional experience may be found in an analysis of publications focusing on the subject. The present review was based on two databases "Web of science" and "Medline" (2000-2011). Initially, 372 abstracts were taken into account. Subsequently, 42 articles were thoroughly studied. The analyzed material represented both experimental and research approaches to the problem. The experimental approach was based on tests carried out on animals in laboratories, whereas the research approach was based on the observations of patients admitted to hospitals with injuries. The literature overview indicates a neuroprotective feature of alcohol and an improved prognosis in intoxicated people suffering from isolated head injuries, even though the severity of their injuries is much higher than in the cases of sober people. In cases of polytrauma injuries, the influence of alcohol is explicitly negative, but does not increase mortality.

[Atypical form of the Simon's symptom in the case of accidental hanging of an 11-year-old boy]. / Nietypowa odmiana objawu Simona u 11-letniego chlopca, który ulegl przypadkowemu powieszeniu.

The repot describes a case of death of an 11-year old boy who died due to fatal accidental hanging from a noose at the attic floor.

[Death of a 57-year old male with previously undiagnosed displacement of the abdominal organs to the chest]. / Zgon 57 letniego mezczyzny z powodu niezdiagnozowanego przemieszczenia narzadów jamy brzusznej do klatki piersiowej.

The report describes a death of a 57-year old male who died due to exacerbated cardiac and pulmonary insufficiency caused by the displacement of the abdominal organs to the chest through a previously undiagnosed diaphragmatic hernia.