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The management of patients undergoing stem cell transplantation requires a multipurpose central venous catheter (CVC) to facilitate drug administration, parenteral nutrition, transfusion of blood products, and collection of blood samples. Peripherally inserted central venous catheters (PICCs) appear to meet these requirements but are rarely used for stem cell infusion. We aimed to retrospectively assess the safety and feasibility of stem cell infusion through PICC and to evaluate its impact on transplantation kinetics. We retrospectively analyzed the outcomes of peripheral blood stem cell (PBSC) transplantation in patients receiving cryopreserved autologous or allogeneic PBSC by PICCs and compared the results with patients receiving transplants through a conventionally inserted central venous catheter (CICC). Despite statistically significant differences in CD34+ dose, infusion rate, and total length of administration, the clinical outcomes of transplantation, exemplified by platelet and neutrophil engraftment, along with the length of hospitalization, were not affected by the prolonged infusion time and lower infusion velocity in the PICC group. Our study showed that the clinical outcomes of PBSC transplantation did not differ between the PICC and CICC groups, suggesting that both types of catheters can be implemented in a PBSC transplantation setting.

Infections are still a major reason of morbidity and one of the most common causes of death after hematopoietic cell transplantation (HCT). Antimicrobial prophylaxis plays a crucial role in decreasing non-relapse mortality after HCT. The objective of this guideline paper is presentation of current recommendations of antimicrobial prophylaxis for children and adults after hematopoietic cell transplantation, prepared in cooperation of Polish scientific hematological societies. Recommendations were prepared by the working group and finally approved by all 23 Polish transplant centers for children and adults. Existing ECIL (European Conference on Infections in Leukemia) and EBMT (European Society of Blood and Marrow Transplantation) guidelines, as well as results of survey performed among all Polish transplant centers, were the background material for working group. Recommendations are presented in sections dedicated to antibacterial prophylaxis, antifungal prophylaxis, antiviral prophylaxis, as well as prophylaxis of toxoplasmosis and infections with Pneumocystis jiroveci. Recommendations on principles of vaccination against COVID-19 are provided based on the state of knowledge in September 2021. A section on guidelines of environmental prophylaxis is also presented.

For many years, intensive research has been carried out on the in-depth understanding of the pathogenesis of multiple myeloma (MM). Nevertheless, the multifactorial nature of the disease, the development of drug resistance, and the side effects of therapy, make it difficult to effectively treat patients. One of the many factors involved in the pathogenesis of MM is brain-derived neurotrophic factor (BDNF). This factor is widely described as a neuroregenerative and neuroprotective agent, but it also regulates non-neuronal cell functions, such as proliferation, apoptosis, and viability. Therefore, BDNF appears to be a good therapeutic target in MM. On the other hand, its decreased concentration during treatment closely correlates with the development of peripheral neuropathy (PN). BDNF dualism requires a detailed understanding of its action on individual molecular mechanisms. Perhaps the optimization of the BDNF level will contribute to the improvement of MM treatment and the reduction of chemotherapy side effects.

Background and purpose: The course of an ischemic stroke depends on many factors. The influence of periodontal diseases and the stimulation of salivation on the course and severity of stroke remains unresolved. Therefore, the aim of the study was to analyze the severity of ischemic stroke depending on the occurrence of periodontal diseases and saliva stimulation. Methods: The severity of the neurological condition was assessed using the NIHSS scale on days one, three and seven of stroke. The incidence of periodontal diseases was classified using the Hall’s scale in the first day of stroke. On days one and seven of stroke, the concentration of IL-1β, MMP-8, OPG and RANKL in the patients’ saliva was assessed using the Elisa technique. At the same time, the level of CRP and the number of leukocytes in the peripheral blood were tested on days one, three and seven of the stroke, and the incidence of upper respiratory and urinary tract infections was assessed. Results:100 consecutive patients with their first ever ischemic stroke were enrolled in the study. 56 randomly selected patients were subjected to the stimulation of salivation, the remaining patients were not stimulated. In the study of the severity of the neurological condition using the NIHS scale on days three and seven of stroke, the degree of deficit in patients without periodontal disease significantly improved compared to patients with periodontal disease, respectively (p < 0.01 and p = 0.01). Patients from the stimulated group had more severe neurological deficit at baseline (p = 0.04). On days three and seven of neurological follow-up, the condition of patients from both groups improved with a further distinct advantage of the unstimulated group over the stimulated group, respectively (p = 0.03 and p < 0.001). In patients from both groups, a statistically significant decrease in CRP and lymphocyte levels was observed on day seven in relation to day one. Conclusions: The occurrence of periodontal disease in a patient with stroke affects the severity of stroke. Stimulation of the mouth and salivary glands in these patients may have a positive effect on the course of stroke, taking into account the dynamics of neurological symptoms.

Introduction: Regenerative capacity of the heart is limited, and the post-infarct left ventricle (LV) dysfunction is associated with poor prognosis. Administration of stem/progenitor cells (SPCs) is a promising approach for cardiac regeneration. Objectives: In the study, we assessed LV function and post-infarcted remodeling in patients with ST-elevated myocardial infarct (STEMI) who received autologous lineage-negative (LIN-) SPCs. Patients and methods: Patients with STEMI and one-vessel coronary artery disease treated with percutaneous revascularisation were divided into study group (LIN- group, 15 patients) that received standard therapy and autologous BM-derived LIN- SPCs and control group (standard therapy group, 19 patients). The cells were administered intracoronary 24 hours after STEMI. The follow-up was 12 months with subsequent non-invasive tests and laboratory parameter evaluation on days 1st, 3rd, and 7th as well as at 1st, 3rd, 6th and 12th month after STEMI. Results: All procedures related to SPCs administration were well tolerated by the patients. In 12-month follow-up, there were no major adverse cardiac events connected with LIN- SPCs administration. During 12-month follow-up, 9 patients from LIN- group (Responders) achieved an improvement in LV ejection fraction (>10% after 12 months) with no signs of unfavorable LV remodeling. Laboratory parameters analysis showed that Troponin T levels were significantly lower until day 7th in the Responders group, while brain natriuretic peptide (BNP) level remained significantly lower from day 3rd to 12th month respectively. Conclusions: Intracoronary infusion of autologous BM-derived LIN- stem/progenitor cells is feasible and safe for patient. Improvement in LV function and prevention of unfavorable remodeling in the 60% of study group seems relatively promising. Stem cell-based therapy for cardiac regeneration still needs more accurate and extensive investigations to estimate and improve their efficacy.

Bortezomib-induced peripheral neuropathy (BiPN) occurs in approximately 40% of patients with multiple myeloma. The induction of severe neuropathy entails the dose reduction or complete elimination of bortezomib (BTZ). Interestingly, discontinuation of BTZ mostly results in a reduction or complete resolution of peripheral neuropathy (PN) symptoms. Therefore, it is likely that the BiPN mechanisms are based on temporary/reversible changes such as epigenetic alterations. In this study, we examined the effect of treating nerve cells, differentiated from the Lund human mesencephalic (dLUHMES) cell line, with several low-dose BTZ (0.15 nM) applications. We showed a significant decrease in global histone H3 acetylation as well as histone H3 lysine 9 acetylation. Moreover, analysis of the genetic microarray showed changes mainly in epigenetic processes related to chromatin rearrangement, chromatin silencing, and gene silencing. GSEA analysis revealed three interesting signaling pathways (SIRT1, B-WICH and, b-Catenin) that may play a pivotal role in PN development. We also performed an analysis of the miRNA microarray which showed the interactions of miR-6810-5p with the genes MSN, FOXM1, TSPAN9, and SLC1A5, which are directly involved in neuroprotective processes, neuronal differentiation, and signal transduction. The study confirmed the existence of BTZ-induced complex epigenetic alterations in nerve cells. However, further studies are necessary to assess the reversibility of epigenetic changes and their potential impact on the induction/resolution of PN.

Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for approximately 1% of all cancers. Despite the initial poor prognosis for MM patients, their life expectancy has improved significantly with the development of novel agents. Immunomodulatory drugs (IMiDs) are widely used in MM therapy. Their implementation has been a milestone in improving the clinical outcomes of patients. The first molecule belonging to the IMiDs was thalidomide. Subsequently, its novel derivatives, lenalidomide (LEN) and pomalidomide (POM), were implemented. Almost all MM patients are exposed to LEN, which is the most commonly used IMiD. Despite the potent anti-MM activity of LEN, some patients eventually relapse and become LEN-resistant. Drug resistance is one of the greatest challenges of modern oncology and has become the main cause of cancer treatment failures. The number of patients receiving LEN is increasing, hence the problem of LEN resistance has become a great obstacle for hematologists worldwide. In this review, we intended to shed more light on the pathophysiology of LEN resistance in MM, with particular emphasis on the molecular background. Moreover, we have briefly summarized strategies to overcome LEN resistance and we have outlined future directions.

ALS remains a fatal, neurodegenerative motor neuron disease. Numerous studies seem to confirm that innate immune system is involved in the pathophysiology of ALS. Hence, the assessment of the complement system and attempts to modify its activity remain the target of medical intervention in ALS. In the present study, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin–) cells were performed every 6 weeks in 20 sporadic ALS patients. The concentrations of various complement components in the cerebrospinal fluid and plasma at different time points after cell injection were quantified using a Luminex multiplex. The results of the complement system were correlated with the level of leukocytes, neutrophils, lymphocytes, fibrinogen and CRP in the peripheral blood and the functional status of ALS patients using Norris and ALS-FRSr scales. The study showed a statistically significant decrease in plasma C3b concentration in all 7th days after cell application. In parallel, a peak decrease in neutrophil count and CRP level was observed on days 5–7, with a simultaneous maximum clinical improvement on days 7–28 of each Lin– cell administration. Adjuvant Lin– cell therapy appears to have the silencing potential on the complement-mediated immune system and thus suppress pro-inflammatory reactions responsible for neurodegeneration. However, further in-depth studies are necessary to address this issue.

The launch of novel chemotherapeutic agents—in particular, proteasome inhibitors and immunomodulatory drugs—dramatically changed multiple myeloma (MM) therapy, improving the response rate and prolonging progression-free survival. However, none of the anti-MM drugs are deprived of side effects. Peripheral neuropathy (PN) seems to be one of the most pressing problems. Despite extensive research in this area, the pathogenesis of drug-induced peripheral neuropathy (DiPN) has not yet been fully elucidated. In the present study, we aimed to assess the potential relationship between proinflammatory factors and the development of PN in MM patients with particular emphasis on the application of VTD (bortezomib, thalidomide, dexamethasone) regimen. Our analysis identified increased concentrations of CCL2, IL-1β, and IFN-γ in plasma of MM patients during treatment, both with and without symptoms of PN, compared with untreated neuropathy-free MM patients. At the same time, the plasma concentration of IL-1β in patients with neuropathy was significantly increased compared with patients without PN before and during treatment. Moreover, the results were enhanced at the transcript level by performing global mRNA expression analysis using microarray technology. The most significant changes were observed in the expression of genes responsible for regulating immunological and apoptotic processes. An in-depth understanding of the mechanisms responsible for the development of DiPN might in the future reduce the incidence of PN and accelerate diagnosis, allowing the choice of neuropathy-free treatment strategies for MM.

We present an extremely rare case report of a 29-year-old multiple myeloma patient with central nervous system involvement and secondary hemophagocytic lymphohistiocytosis (HLH). We observed that HLH was presumably triggered by the immunomodulatory drug—lenalidomide. HLH is frequently misdiagnosed or underdiagnosed. As HLH requires immediate treatment, our report emphasizes the need to consider HLH in the differential diagnosis when the condition of a patient receiving chemotherapy rapidly deteriorates and an infectious etiology is excluded. We furthermore discuss the pathogenesis of HLH, with particular emphasis on drugs affecting the immune system as well as possible therapeutic strategies.

The exact pathophysiology of severe COVID-19 is not entirely elucidated, but it has been established that hyperinflammatory responses and cytokine storms play important roles. The aim of this study was to examine CMV status, select chemokines, and complement components in COVID-19, and how concentrations of given molecules differ over time at both molecular and proteomic levels. A total of 210 COVID-19 patients (50 ICU and 160 non-ICU patients) and 80 healthy controls were enrolled in this study. Concentrations of select chemokines (CXCL8, CXCL10, CCL2, CCL3, CCR1) and complement factors (C2, C9, CFD, C4BPA, C5AR1, CR1) were examined at mRNA and protein levels with regard to a COVID-19 course (ICU vs. non-ICU group) and CMV status at different time intervals. We detected several significant differences in chemokines and complement profiles between ICU and non-ICU groups. Pro-inflammatory chemokines and the complement system appeared to greatly contribute to the pathogenesis and development of severe COVID-19. Higher concentrations of CXCL8 and CCL2 in the plasma, with reduced mRNA expression presumably through negative feedback mechanisms, as well as CMV-positive status, correlated with more severe courses of COVID-19. Therefore, CXCL8, CCL2, and CMV seropositivity should be considered as new prognostic factors for severe COVID-19 courses. However, more in-depth research is needed.

Multiple myeloma (MM) is a malignant, incurable neoplastic disease. The currently used treatment significantly improves the prognosis and extends the survival time of patients. Unfortunately, a common side effect of the therapy is peripheral neuropathy, which may lead to dose reduction or complete treatment discontinuation/modification. In this study, we examined the changes in plasma levels of circulating miRNAs in myeloma patients to define potential factors characteristic for drug-induced peripheral neuropathy (DiPN). Global miRNA expression profile in the plasma of patients with MM during treatment was determined using miRNA microarray technology. Receiver operating characteristic (ROC) analysis allowed the identification of three miRNAs (miR-22-3p; miR-23a-3p; miR-24-3p) that could be a potential biomarker of PN. The most promising results were obtained for miR-22-3p, which was characterized by ROC area under curve (AUC) = 0.807. Our results suggest a relationship between the DiPN in patients with MM and the level of selected miRNAs in the plasma.

Background Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of a rapid course. In 25% of ALS sufferers, speech disorders occur as prodromal symptoms of the disease. Impaired communication affects physical health and has a negative impact on mental and emotional condition. In this study, we assessed which domains of speech are particularly affected in ALS. Subsequently, we estimated possible correlations between the ALS patients’ subjective perception of their speech quality and an objective assessment of the speech organs carried out by an expert. Methods The study group consisted of 63 patients with sporadic ALS. The patients were examined for articulatory functions by means of Voice Handicap Index (VHI) and the Frenchay Dysarthria Assessment (FDA). Results On the basis of the VHI scores, the entire cohort was divided into 2 groups: group I (40 subjects) with mild speech impairment, and group II (23 subjects) displaying moderate and profound speech deficits. In an early phase of ALS, changes were typically reported in the tongue, lips and soft palate. The FDA and VHI-based measurements revealed a high, positive correlation between the objective and subjective evaluation of articulation quality. Conclusions Deterioration of the articulatory organs resulted in the reduction of social, physical and emotional functioning. The highly positive correlation between the VHI and FDA scales seems to indicate that the VHI questionnaire may be a reliable, self-contained tool for monitoring the course and progression of speech disorders in ALS. Trial registration NCT02193893.

Background. Autologous bone marrow-derived lineage-negative (Lin−) cells present antiapoptotic and neuroprotective activity. The aim of the study was to evaluate the safety and efficacy of novel autologous Lin− cell therapy during a 12-month follow-up period. Methods. Intravitreal injection of Lin− cells in 30 eyes with retinitis pigmentosa (RP) was performed. The fellow eyes (FEs) were considered control eyes. Functional and morphological eye examinations were performed before and 1, 3, 6, 9, and 12 months after the injection. Results. Patients whose symptoms started less than 10 years ago gained 14 ± 10 letters, while those with a longer disease duration gained 2.86 ± 8.54 letters compared to baseline at the 12-month follow-up ( p = 0.021 ). There were significantly higher differences in response densities of P 1 -wave amplitudes in the first ring of multifocal ERGs in treated eyes than FE recordings in all follow-up points were detected. Accordingly, the mean deviation in 10-2 static perimetry improved significantly in the treated eyes compared with fellow eyes 12 months after the procedure. The QoL scores improved significantly and lasted until the 9-month visit. Conclusion. Lin− cell-based therapy is safe and effective, especially for a well-selected group of RP patients who still maintained good function of the foveal cones.

Multiple myeloma (MM) is a plasma cell malignancy with multifactorial etiology. One of the underlying mechanisms is immune system dysregulation. Immunotherapy is being widely introduced into various MM treatment protocols. Nevertheless, little is known about boosting the immune system with supportive treatment. Although classical actions of vitamin D (VD) are very well established, their non-classical actions related to the modulation of the immune system in MM are still a subject of ongoing research. In this literature review, we intend to summarize research conducted on VD and MM, both in vitro and in vivo, with particular emphasis on immune system modulation, the induction of the differentiation of malignant MM cells, synergic activity with anti-MM drugs, and MM-associated peripheral neuropathy.

Background and objectives: Speech disorders are observed in 30% of newly diagnosed sporadic amyotrophic lateral sclerosis (ALS) patients. Characterized by a dynamic course, dysfunction of articulation has not so far been well understood. The aim of this study was to analyze the influence of demographic factors (sex, age, duration of the disease) and concomitant diseases (degenerative spine disease, depression, hypertension, hypothyroidism, hyperthyroidism, and allergy) on the functioning of speech organs in ALS patients. Materials and Methods: The study group consisted of 65 patients with sporadic ALS. Patients were examined for articulatory functions by means of the Frenchay Dysarthria Assessment (FDA). Results: 68% of the study sample had spinal disorders. Logistic regression analysis showed that a decline in the functioning of lips, soft palate, length of phonation, and voice loudness was more common among men. Patients diagnosed with degenerative spine disease more often suffered from respiratory disorders, while younger patients (&lt, 60 years of age) significantly more often had the impairment of the sentence and spontaneous speech functions. Conclusions: The male gender in patients with ALS is associated with an increased risk of deterioration of the phonation length function. Patients under 60 years of age are associated with more often pronouncing sentences disorders and spontaneous speech disorders.

Therapeutic interventions in amyotrophic lateral sclerosis (ALS) are still far from satisfying. Immune modulating procedures raise hopes for slowing the disease progression. Stem cell therapies are believed to possess the ability to regulate innate and adaptive immune response and inflammation processes. Hence, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin&ndash, ) cells were performed every six weeks in 40 sporadic ALS patients. The concentrations of inflammatory-related proteins and expression profiles of selected miRNA in the cerebrospinal fluid (CSF) and plasma at different timepoints post-transplantation were quantified by multiplex Luminex and qRT-PCR. The global gene expression in nucleated blood cells was assessed using the gene microarray technique. According to the ALS Functional Rating Scale (FRSr), the study population was divided into responders (group I, n = 17) and non-responders (group II, n = 23). A thorough analysis of the pro-inflammatory expression profiles, regulated miRNA pathways, and global gene expression profiles at the RNA level revealed the local and systemic effects of Lin&ndash, cell therapy on the immune system of patients with ALS. The autologous application of Lin&ndash, cells in CSF modulates immune processes and might prevent the progression of neurodegeneration. However, further in-depth studies are necessary to confirm the findings, and prolonged intervention is needed to maintain therapeutic effects.

Background: Amyotrophic lateral sclerosis (ALS) is one of the most frequently occurring neurodegenerative diseases affecting speech and swallowing. This preliminary study aimed to investigate whether an autologous lineage-negative stem/progenitor cell therapy applied to ALS patients affects the level of selected trophic and proinflammatory factors, and subsequently improves the articulation. Methods: We enrolled 12 patients with sporadic ALS, who underwent autologous bone marrow-derived lineage negative (LIN-) cells administration into cerebrospinal fluid (CSF). We evaluated patients' articulation using the Frenchay Dysarthria Assessment on days 0 and 28 following the LIN- cells administration. Concentrations of various factors (BDNF, NGF, ANGP-2, VEGF, PDGF-AA, PEDF, COMP-FH, CRP, C3, C4) in CSF were quantified by multiplex fluorescent bead-based immunoassays in the samples collected on the day of LIN- cells administration and 28 days later. On top of this, we assessed levels of BDNF and NGF in the patients' plasma on the day of the injection, three, seven days and three months after the treatment. Results: Of the 12 patients who received the LIN- cell therapy 8 showed short-termed improvement in articulatory functions (group I), which was particularly noticeable in better phonation time, lips and soft palate performance, swallowing reflex and voice loudness. Four patients (group II) did not show substantial improvement. CSF concentrations of BDNF, ANGP-2 and PDGF-AA in group I decreased significantly 28 days after LIN- cells administration. The highest concentration levels of BDNF in group II and NGF in both groups in blood plasma were observed on day 3 following the injection. Conclusions: The outcomes of the LIN- cell application in ALS treatment of articulatory organs are promising. The procedure proved to be safe and feasible. A short-lasting trophic effect of autologous LIN- administration could encourage repeated cell's application in order to sustain their beneficial effects, however this approach needs further investigation.

Background: Speech disorders are observed in 30% of newly diagnosed sporadic amyotrophic lateral sclerosis (ALS) patients. Characterized by a dynamic course, dysfunction of articulation has not so far been well understood. The aim of this study was to analyze the influence of sociodemographic factors (sex, age, duration of the disease) and concomitant diseases (degenerative spine disease, depression, hypertension, hypothyroidism, hyperthyroidism, and allergy) on the functioning of speech organs in ALS patients.Methods: The study group consisted of 65 patients with sporadic ALS. Patients were examined for articulatory functions by means of the Frenchay Dysarthria Assessment (FDA). Results: 68% of the study sample had spinal disorders. Logistic regression analysis showed that a decline in the functioning of lips, soft palate, length of phonation and voice loudness was more common among men. Patients diagnosed with degenerative spine disease more often suffered from respiratory disorders, while younger patients (< 60 years of age) significantly more often had the impairment of the sentence and spontaneous speech functions.Conclusions: The male sex and young age of ALS patients substantially increase the risk of progression of the impairment of speech organs (such as lips, soft palate) and functions (length of phonation, voice loudness, sentence, spontaneous speech). Degenerative spondylogenic changes in the spinal column deteriorated respiratory problems in patients with ALS.

Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin&minus, ) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin&minus, cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations.

Amyotrophic lateral sclerosis (ALS) remains a fatal, neurodegenerative disease frequently leading to dysarthria and impaired swallowing. Better understanding of ALS pathophysiology is prompting the use of humoral cell therapies. Hence, a repeated cellular therapy was applied to ALS patients as an attempt to prevent speech deterioration. Autologous bone marrow-derived lineage-negative (Lin−) cells were intrathecally administered three times at six-week intervals to 42 sporadic ALS patients. Patients were examined for articulatory functions using subjective (VHI) and objective (FDA) scales. Selected trophic, proinflammatory factors and expression profiles of miRNA were measured in cerebrospinal fluid (CSF) and plasma by multiplex Luminex and q-PCR in different timepoints. Of the 42 patients who received the Lin− cells, 6 showed improvement in articulatory functions, 27 remained stable, and 9 deteriorated after 18 weeks of therapy according to FDA scale. Clinical improvement was particularly evident by the 7th day of each cell application and concerned better cough and swallow reflex, soft palate, laryngeal time, pitch, and volume. These results correlated with significant changes in the concentration of various trophic and proinflammatory factors and miRNA expression profiles. A multiple application of Lin− cells proved to be safe and feasible. The repeated procedure can potentate a humoral effect and prevent speech deterioration. A short-lasting trophic effect of each Lin− cells administration was observed on local and systemic level. However, further in-depth studies are necessary to sustain the beneficial effect.

We present a unique case of a young woman with acute myeloid leukemia (AML) with complex karyotype. The presence of the t(4;11)(q23;p15) is extremely rare in myeloid leukemias, while t(4;8)(q32;q13) has not yet been described in any leukemia reference. Another interesting issue is the familial aggregation of myeloid malignancies and worse course of the disease in each subsequent generation, as well as an earlier onset of the disease. Our report emphasizes the need for thorough pedigree examination upon myeloid malignancy diagnosis as there are relatives for whom counseling, gene testing, and surveillance may be highly advisable.

We present one of few cases of COVID-19 occurrence during the early phase of autologous hematopoietic stem cell transplantation. We observed an interesting correlation between the patient’s rapid clinical deterioration and myeloid reconstitution that cannot be assigned to engraftment syndrome. Our report emphasizes the need to investigate whether timely steroid therapy upon neutrophil engraftment in the setting of COVID-19 could limit the extent of lung injury and prevent ARDS. Furthermore, we discuss a significant issue of possible prolonged incubation of the virus in heavily pretreated hematological patients.

Cell therapy raises hope to reduce the harmful effects of acute myocardial ischemia. Stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed the plasma levels of selected trophic factors in patients undergoing application of autologous bone marrow (BM)-derived, lineage-negative (Lin&minus, ) stem/progenitor cells into the coronary artery in the acute phase of myocardial infarction. The study group consisted of 15 patients with acute myocardial infarction (AMI) who underwent percutaneous revascularization and, afterwards, Lin&minus, stem/progenitor cell administration into the infarct-related artery. The control group consisted of 19 patients. BM Lin&minus, cells were isolated using immunomagnetic methods. Peripheral blood was collected on day 0, 2, 4, and 7 and after the first and third month to assess the concentration of selected trophic factors using multiplex fluorescent bead-based immunoassays. We found in the Lin&minus, group that several angiogenic trophic factors (vascular endothelial growth factor, Angiopoietin-1, basic fibroblast growth factor, platelet-derived growth factor-aa) plasma level significantly increased to the 4th day after myocardial infarction. In parallel, we noticed a tendency where the plasma levels of the brain-derived neurotrophic factor were increased in the Lin&ndash, group. The obtained results suggest that the administered SPCs may be a valuable source of angiogenic trophic factors for damaged myocardium, although this observation requires further in-depth studies.

Introduction. Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease, leading to loss of muscle strength and motor control. Impaired speech and swallowing lower the quality of life and consequently may induce acute respiratory failure. Bone marrow-derived stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed whether adjuvant cellular therapy could affect the levels of selected neurotrophins and proinflammatory factors in the cerebrospinal fluid (CSF) and subsequently prevent the deterioration of articulation.Materials and Methods. The study group consisted of 32 patients with sporadic ALS who underwent autologous lineage-negative (Lin−) stem cell intrathecal administration to the spinal canal. Lin−cells were aspirated from the bone marrow and isolated using immunomagnetic beads and a lineage cell depletion kit. Patients were examined for articulatory functions by means of the Voice Handicap Index (VHI) questionnaire and Frenchay Dysarthria Assessment (FDA). In parallel, we carried out the analysis of selected trophic and proinflammatory factors in CSF utilizing multiplex fluorescent bead-based immunoassays.Results. Of the 32 patients who received the Lin−progenitor cell therapy, 6 (group I) showed improvement in articulatory functions, 23 remained stable (group II), and 3 deteriorated (group III) on the 28thday. The improvement was particularly noticeable in a better cough reflex, laryngeal time, and dribble reflex. A statistically significant lower level of brain-derived neurotrophic factor (BDNF) was observed on day 0 in group I compared to group II. The CSF concentrations of C-reactive protein (CRP) in group I significantly decreased 7 days after Lin−SPC transplantation. On the contrary, a significant increase in the tumor necrosis factor receptor (TNF-R) level was confirmed among patients from group I with improvement of dribble and coughing reflex, tongue movements, and respiration on the 7thday, as well as on day 28 including dribble reflex solely.Conclusions. An application of Lin−stem cells could potentate the beneficial humoral effect. The prevention of deterioration of articulatory functions in ALS patients after applying adjuvant Lin−stem cell therapy seems to be promising. Although the procedure is safe and feasible, it requires further in-depth studies.

Therapeutic options for amyotrophic lateral sclerosis (ALS) are still limited. Great hopes, however, are placed in growth factors that show neuroprotective abilities (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF)) and in the immune modulating features, in particular, the anti-inflammatory effects. In our study we aimed to investigate whether a bone marrow-derived lineage-negative (Lin-) cells population, after autologous application into cerebrospinal fluid (CSF), is able to produce noticeable concentrations of trophic factors and inflammatory-related proteins and thus influence the clinical course of ALS. To our knowledge, the evaluation of Lin- cells transplantation for ALS treatment has not been previously reported. Early hematopoietic Lin- cells were isolated from twelve ALS patients’ bone marrow, and later, the suspension of cells was administered into the subarachnoid space by lumbar puncture. Concentrations of selected proteins in the CSF and plasma were quantified by multiplex fluorescent bead-based immunoassays at different timepoints post-transplantation. We also chose microRNAs (miRNAs) related to muscle biology (miRNA-1, miRNA-133a, and miRNA-206) and angiogenesis and inflammation (miRNA-155 and miRNA-378) and tested, for the first time, their expression profiles in the CSF and plasma of ALS patients after Lin- cells transplantation. The injection of bone marrow cells resulted in decreased concentration of selected inflammatory proteins (C3) after Lin- cells injection, particularly in patients who had a better clinical outcome. Moreover, several analyzed miRNAs have changed expression levels in the CSF and plasma of ALS patients subsequent to Lin- cells administration. Interestingly, the expression of miR-206 increased in ALS patients, while miR-378 decreased both in the CSF and plasma one month after the cells’ injection. We propose that autologous lineage-negative early hematopoietic cells injected intrathecally may be a safe and feasible source of material for transplantations to the central nervous system (CNS) environment aimed at anti-inflammatory support provision for ALS adjuvant treatment strategies. Further research is needed to evaluate whether the observed effects could significantly influence the ALS progression.

We investigated effects of bone marrow-derived, lineage-negative cell (Lin−BMC) transplantation in acute retinal injury. Lin−BMCs were intravitreally injected into murine eyes at 24 h after NaIO3-induced injury. Morphology, function, and expression of apoptosis-related genes, including brain-derived neurotrophic factor (BDNF) and its receptor, were assessed in retinas at 7 days, 28 days, and 3 months after transplantation. Moreover, global gene expression at day 7 was analyzed by RNA arrays. We observed that Lin−BMCs integrated into outer retinal layers improving morphological retinal structure and induced molecular changes such as downregulation of proapoptoticcaspase-3gene, a decrease inBAX/BCL-2gene ratio, and significant elevation ofBDNFexpression. Furthermore, transplanted Lin−BMCs differentiated locally into cells with a macrophage-like phenotype. Finally, Lin−BMCs treatment was associated with generation of two distinct transcriptomic patterns. The first relates to downregulated genes associated with regulation of neuron cell death and apoptosis, response to oxidative stress/hypoxia and external stimuli, and negative regulation of cell proliferation. The second relates to upregulated genes associated with neurological system processes and sensory perception. Collectively, our data demonstrate that transplanted Lin−BMCs exert neuroprotective function against acute retinal injury and this effect may be associated with their antiapoptotic properties and ability to express neurotrophic factors.

Background Donor-related neoplasms are a potential complication of treatment strategies involving stem cell transplantation. Although mechanisms for detection of short-term complications after these procedures are well developed, complications with delayed onset, notably transmission of chronic diseases such as chronic myeloid leukemia (CML), have been difficult to assess. Consequently, we studied the potential of human CML cells to engraft hematopoietic tissues after intravenous implantation in mice. Methods Human peripheral blood cells, collected from CML patients presenting with moderately increased white blood cells count before treatment, were transplanted into sub-lethally irradiated, immunodeficient mice. Five weeks after transplantation the nuclear cells were isolated from the murine bone marrow, spleen, and peripheral blood and were used to quantitatively detect human CD45 antigen by flow cytometry; qRT-PCR was used to detect the BCR-ABL1 fusion gene, and the human or murine beta-glucuronidase housekeeping gene was used to examine human-murine chimerism. Results We found that all evaluated animals had donor chimerism at the selected interval after transplant and the presence of a specific BCR-ABL1 fusion gene transcript was also detected. Conclusions Our results suggest that the risk of neoplasm transmission cannot be eliminated during hematopoietic stem cell transplantation from undiagnosed CML donors with borderline leukocytosis. The obtained data confirms the potential of leukemic cells to viably engraft the hematopoietic organs post-transplantation in an immunosuppressed recipient.

The retinal pigment epithelium (RPE) has been reported to demonstrate feasible self-regenerative potential under specific conditions. However, the precise underlying mechanisms involved in this process are still elusive. Here, we performed a sequential morphological, molecular, and functional analysis of retinal injury and subsequent tissue regeneration after intravenous administration of a low dose of sodium iodate (15?mg/kg) in mice over long-term observation, up to 3 months post-injury. To assess the kinetics of the injury/recovery process, the electroretinography (ERG) responses were correlated with ongoing alterations in retinal structure and the global gene expression profile of injured retinas using genome-wide RNA microarray technology, western blotting and immunohistochemical analyses. We observed considerable improvement in the rod cell-mediated ERG response, which was accompanied by the regeneration of RPE within the injury site by the 3rd month post-injury. Our results confirm that the repairing mechanisms within injured retinas involve a significant glial cell reaction marked by glial cell proliferation, migration from their original location toward the injury site, followed by a significant overproduction of NTs such as BDNF, GDNF and NT-3. The global gene expression analysis revealed that initially up-regulated genes associated with cell death, apoptosis, acute response to stress pathways underwent considerable down-regulation in the late post-injury period. Accordingly, the genes implicated in nervous tissue remodeling and neuron development, the regulation of synaptic transmission and the establishment of localization were substantially induced by the 3rd month. Collectively, our observations support the view that M?ller glial cells might well play an active role not only in retinal cell reorganization following injury but potentially also in RPE regeneration, which appears to be the key event in retinal reparative process. Furthermore, we provided novel compelling evidence of the crucial role of neurotrophins in the pathophysiology of retinal repair and identified the signaling pathways that are activated during this process.

BACKGROUND The demand for human hematopoietic stem and progenitor cells (HSPCs) for transplantation is increasing. Thus, effective alternative sources of HSPCs are required. Consequently, we sought to expand the accessibility of hematopoietic cells for clinical purposes by the investigation of hematopoietic reconstitution after transplantation of human HSPCs harvested from the bone marrow (BM) of heparinized deceased organ donors (HDODs). METHODS For multipart research comparison, human BM HDODs-, healthy donor-derived, umbilical cord blood nuclear cells, or CD34(+) cells were transplanted into sublethally irradiated NOD/SCID mice. Twenty-eight days after transplantation nuclear cells were isolated from the murine BM, spleen, and peripheral blood and were used to quantitatively detect human CD45 antigen by quantitative real-time reverse transcriptase-polymerase chain reaction and flow cytometry. The clonogenic growth of human colony-forming units was also investigated. RESULTS We found that umbilical cord blood-derived HSPCs showed the greatest transplantation potential in our in vivo model. Interestingly, the transplantation potential of HSPCs collected from the BM of HDODs was of the same quality as cells obtained from healthy BM donors. CONCLUSION Based on these results, we conclude that HDODs are a strongly underappreciated source of HSPCs that are ready to use for clinical purposes.

Stem cell regeneration of damaged tissue has recently been reported in many different organs. Here, we investigated the mobilization of different stem/progenitor cell (SPC) populations into the peripheral blood (PB), their subsequent homing to the injured retina (IR) and contribution to its regeneration in a retinal pigment epithelium (RPE) damage model induced by sodium iodate (NaIO(3)).Mobilization of SPCs was evaluated by flow cytometry. SPCs distribution in IR was assessed using bone marrow (BM)-derived GFP(+)Lin(-) cells transplanted intravenously into NaIO(3)-treated C57Bl/6 mice. The quantity of the chemokine SDF-1 in PB and IR was measured by ELISA and qRT-PCR, respectively. Apoptosis (TUNEL assay), cell proliferation (PCNA analysis) as well as functional retinal activity (electroretinogram) were examined at several time points after NaIO(3) administration.Mobilization of SPCs along with the highest cell proliferation and massive apoptosis within IR were observed on the third day after NaIO(3) administration. Similarly, donor GFP(+)Lin(-) cells were detected in the retina as soon as day 4 after NaIO(3) injection. Plasma levels of SDF-1 did not differ significantly in mice exposed to NaIO(3) compared to healthy controls, however mRNA for SDF-1 was overexpressed locally in IR. Functional retinal recovery was not achieved.Our study provides evidence that BM SPCs egress into PB and home to the injured retina, but are not capable of restoring its function. These results indicate that if the range of retinal destruction is profound, endogenous regeneration is ineffective and may ultimately require adjuvant therapeutic transplantation of specific SPCs subpopulations.

Stem cells (SCs) maintain the balance among somatic cell populations in various tissues and are responsible for organ regeneration. The remarkable progress of regenerative medicine in the last few years indicates promise for the use of SCs in ophthalmic disorder treatment. This review describes the current view on hierarchy in the SC compartment and presents the latest attempts to use adult SCs in the regeneration of the retina. Research performed primarily in animal models gives hope for using similar strategies in humans. However, the search for the optimal source of SCs for cell therapy continues. We briefly discuss various potential sources of adult SCs that could be employed in regenerative medicine, particularly focusing on recently identified, very small embryonic-like SCs (VSEL-SCs). These cells are even present in the bone marrow and adult tissues of older patients and could be harvested from cord blood. We believe that VSEL-SCs, after the establishment of ex vivo expansion and differentiation protocols, could be harnessed for retina regeneration.

Purpose Retinal degenerative diseases targeting the RPE and adjacent photoreceptors affect millions of people worldwide. The field of stem cell- and gene-based therapy holds great potential for the treatment of such diseases. The present study sought to graft genetically engineered mesenchymal stem cells (MSCs) that continuously produce neurotrophin-4 (NT-4) into the murine eye after the onset of acute retinal injury. Methods C57BL/6 mice were subjected to acute retinal damage using a low dose of sodium iodate (20 mg/kg of body weight), followed by intravitreal injection of lentivirally modified MSC-NT-4 into the right eye. At 3 months after the MSC transplantation grafted cell survival, retinal function and gene expression were analyzed. Results Immunofluorescence analysis confirmed that transplanted MSCs survived for at least 3 months after intravitreal injection and preferentially migrated toward sites of injury within the retina. MSC-NT-4 actively produced NT-4 in the injured retina and significantly protected damaged retinal cells, as evaluated by ERG and optical coherence tomography (OCT). Of importance, the long-term therapy with MSC-NT-4 was also associated with induction of prosurvival signaling, considerable overexpression of some subsets of transcripts, including several members of the crystallin β-γ superfamily (Cryba4, Crybb3, Cryba2, Crybb1, Crybb2, Cryba1, and Crygc) and significant upregulation of biological processes associated with visual perception, sensory perception of light stimulus, eye development, sensory organ development, and system development. Conclusions Transplantation of genetically modified MSCs that produce neurotrophic growth factors may represent a useful strategy for treatment of different forms of retinopathies in the future.

The purpose of this study was to appraise the functional response of damaged retina to the stem cell-based therapy in mice. The majority of disorders leading to the irreversible vision loss in the developed world is caused by retinal degeneration. Since, recent reports emphasized regenerative potential of bone marrow stem marrow stem/progenitor cells (SPCs), we investigated here the beneficial effect of intravenously administrated SPCs on regeneration of acutely injured retina.Selective chemical injury of murine retinas was induced by intravenous administration of sodium iodate (NalO3) in its toxic dose. Flash electroretinogram (ERG), was performed in different time points after infusion of bone marrow-derived and negative for linage antigens population of SPCs.Stem cell-based therapy resulted in gradual increase of b-wave amplitude in ERG recordings starting from the 3rd day after NalO3 administration, what confirmed the improvement of retinal function in long-term observation.Our preliminary findings revealed that the selected stem cell-based therapy employed in the adjuvant mode has been shown to be effective in supporting the retinal function recovery after acute retinal damage.

Objectives: Thyroid hormones mediate many physiological and developmental functions in humans. The role of the 3,3′,5‐triiodo‐l‐thyronine (T3) in normal human haematopoiesis at the cellular and molecular levels has not been determined. In this study, it was revealed that the human haematopoietic system might be directly depended on T3 influence. Materials and methods: We detected the TRα1 and TRβ1 gene expression at the mRNA level in human cord blood, peripheral blood and bone marrow CD34(+)‐enriched progenitor cells, using the RT‐PCR method. Furthermore, we performed Western blotting to prove TRα1 and TRβ1 expression occurs at the protein level in human cord blood, peripheral blood and bone marrow CD34(+) cells. In addition, the examined populations of cells were exposed in serum‐free conditions to increasing doses of T3 and were subsequently investigated for clonogenic growth of granulocyte‐macrophage colony‐forming unit and erythrocyte burst‐forming unit in methylcellulose cultures, and for the level of apoptosis, by employing annexin V staining and the terminal deoxynucleotidyltransferase‐mediated dUTP nick‐end labelling method. We investigated expression levels of apoptosis‐related Bax and antiapoptotic Bcl‐2 and Bcl‐x (L) genes in the examined cells. Results: We found that exposure to higher and lower than normal concentration of thyroid hormone significantly influenced clonogenecity and induced apoptosis in human haematopoietic progenitor cells. Conclusions: This study expands the understanding of the role of thyroid disorders in normal human haematopoiesis and indicates a direct influence of T3 on this process.

Sequential morphological and functional features of retinal damage in mice exposed to different doses (40 vs. 20 mg/kg) of sodium iodate (NaIO(3)) were analyzed. Retinal morphology, apoptosis (TUNEL assay), and function (electroretinography; ERG) were examined at several time points after NaIO(3) administration. The higher dose of NaIO(3) caused progressive degeneration of the whole retinal area and total suppression of scotopic and photopic ERG. In contrast, the lower dose induced much less severe degeneration in peripheral part of retina along with a moderate decline of b- and a-wave amplitudes in ERG, corroborating the presence of regions within retina that retain their function. The peak of photoreceptor apoptosis was found on the 3rd day, but the lower dose induced more intense reaction within the central retina than in its peripheral region. In conclusion, these results indicate that peripheral area of the retina reveals better resistance to NaIO(3) injury than its central part.