Cells Of Origin Research Articles

Iris melanoma in an Australian cohort.

To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival. Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented. The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

CRISPR-Cas9 Gene Editing Therapy, a Curative Hope for Sickle Cell in Nigeria, West Africa

Sickle cell anaemia is one of the haemoglobin abnormalities resulting from a genetic mutation— it is caused by inheriting two faulty genes that result in an abnormal substitution of glutamate for valine on the beta chain of haemoglobin, which causes haemoglobin molecules to stick together. According to a World Health Organization (WHO) report, 20 out of every 1,000 births suffer from sickle-cell anaemia, and 24% of Nigerians are carriers of this mutant gene. Scientists have suggested several solutions, including stem cell transplantation and gene therapies, but these have faced opposition due to ethical beliefs, high cost, and the ensuing immune issues. Research is now centered on advancing genome editing techniques for gene therapy. Ongoing studies have proven that genetic differences can be corrected methodically by modifying the genome at specific sites instead of introducing a new copy of the affected gene into the cells; due to the effectiveness of this method, scientists are testing its applications in manipulating genes in various systems. This review correlates a few studies that used the recently developed technique—CRISPR-Cas9—as a novel approach to gene therapy, dissecting the different clinical studies about sickle cell origin to point out many of its ethical and medical limitations, the consequences of these limitations, and the advancements this technology has made possible.

Pan-cancer Analysis Reveals m6A Variation and Cell-specific Regulatory Network in Different Cancer Types.

As the most abundant messenger RNA (mRNA) modification in mRNA, N 6-methyladenosine (m6A) plays a crucial role in RNA fate, impacting cellular and physiological processes in various tumor types. However, our understanding of the function and role of the m6A methylome in tumor heterogeneity remains limited. Herein, we collected and analyzed m6A methylomes across nine human tissues from 97 m6A sequencing (m6A-seq) and RNA sequencing samples. Our findings demonstrate that m6A exhibits different heterogeneity in most tumor tissues compared to normal tissues, which contributes to the diverse clinical outcomes in different cancer types. We also found that the cancer type-specific m6A level regulated the expression of different cancer-related genes in distinct cancer types. Utilizing a novel and reliable method called "m6A-express", we predicted m6A-regulated genes and revealed that cancer type-specific m6A-regulated genes contributed to the prognosis, tumor origin, and infiltration level of immune cells in diverse patient populations. Furthermore, we identified cell-specific m6A regulators that regulate cancer-specific m6A and constructed a regulatory network. Experimental validation was performed, confirming that the cell-specific m6A regulator CAPRIN1 controls the m6A level of TP53. Overall, our work reveals the clinical relevance of m6A in various tumor tissues and explains how such heterogeneity is established. These results further suggest the potential of m6A for cancer precision medicine for patients with different cancer types.

Comparative single-cell transcriptomic analysis reveals putative differentiation drivers and potential origin of vertebrate retina.

Despite known single-cell expression profiles in vertebrate retinas, understanding of their developmental and evolutionary expression patterns among homologous cell classes remains limited. We examined and compared approximately 240 000 retinal cells from four species and found significant similarities among homologous cell classes, indicating inherent regulatory patterns. To understand these shared patterns, we constructed gene regulatory networks for each developmental stage for three of these species. We identified 690 regulons governed by 530 regulators across three species, along with 10 common cell class-specific regulators and 16 highly preserved regulons. RNA velocity analysis pinpointed conserved putative driver genes and regulators to retinal cell differentiation in both mouse and zebrafish. Investigation of the origins of retinal cells by examining conserved expression patterns between vertebrate retinal cells and invertebrate Ciona intestinalis photoreceptor-related cells implied functional similarities in light transduction mechanisms. Our findings offer insights into the evolutionarily conserved regulatory frameworks and differentiation drivers of vertebrate retinal cells.

Multi-scale brain attributes contribute to the distribution of diffuse glioma subtypes.

Gliomas are primary brain tumors and are among the most malignant types. Adult-type diffuse gliomas can be classified based on their histological and molecular signatures as IDH-wildtype glioblastoma, IDH-mutant astrocytoma, and IDH-mutant and 1p/19q-codeleted oligodendroglioma. Recent studies have shown that each subtype of glioma has its own specific distribution pattern. However, the mechanisms underlying the specific distributions of glioma subtypes are not entirely clear despite partial explanations such as cell origin. To investigate the impact of multi-scale brain attributes on glioma distribution, we constructed cumulative frequency maps for diffuse glioma subtypes based on T1w structural images and evaluated the spatial correlation between tumor frequency and diverse brain attributes, including postmortem gene expression, functional connectivity metrics, cerebral perfusion, glucose metabolism, and neurotransmitter signaling. Regression models were constructed to evaluate the contribution of these factors to the anatomic distribution of different glioma subtypes. Our findings revealed that the three different subtypes of gliomas had distinct distribution patterns, showing spatial preferences toward different brain environmental attributes. Glioblastomas were especially likely to occur in regions enriched with synapse-related pathways and diverse neurotransmitter receptors. Astrocytomas and oligodendrogliomas preferentially occurred in areas enriched with genes associated with neutrophil-mediated immune responses. The functional network characteristics and neurotransmitter distribution also contributed to oligodendroglioma distribution. Our results suggest that different brain transcriptomic, neurotransmitter, and connectomic attributes are the factors that determine the specific distributions of glioma subtypes. These findings highlight the importance of bridging diverse scales of biological organization when studying neurological dysfunction.

Optic nerve infiltration as a significant feature in the treatment of a rare secondary intraocular lymphoma derived from a primary breast B-cell lymphoma: A case report

Intraocular lymphoma (IOL) is a rare form of lymphocytic malignancy which may pose a significant diagnostic challenge as it may masquerade various uveitis entities, with secondary IOL being less common than primary IOL. A 47-year-old woman presented with blurring of the right eye and floaters since 5 months before admission. She had a history of complete remission from primary breast diffuse large B cell lymphoma for five consecutive years. Both eyes had vitreous haziness and several yellowish, thickened retinal lesions with edematous and infiltrated optic nerves. The best-corrected visual acuity was hand movement for the right eye and 6/45 for the left eye. Cytopathologic exam of the vitreous showed a B cell origin lymphoma. Cerebral magnetic resonance imaging revealed new parenchymal lesions suggestive of metastatic lesions. The patient was given multiple rituximab intravitreal injections and systemic chemotherapy. Treatment options for IOL might be influenced by the central nervous system (CNS) involvement, which is signified by infiltration of the optic nerve in this case.

Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline.

Little is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyzed the transmission of early pregastrulation lineages and corresponding mutations across human generations. We found that the germline in NC0 is polyclonal and is founded by at least two cells likely descending from the two blastomeres arising from the first zygotic cleavage. Analyses of public data from several multi-children families and from 1,934 familial quads confirmed this finding in larger cohorts, revealing that known imbalances of up to 90:10 in early lineages allocation in somatic tissues are not reflected in transmission to offspring, establishing a fundamental difference in lineage allocation between the soma and the germline. Analyses of all the data consistently suggest that germline has a balanced 50:50 lineage allocation from the first two blastomeres.

Longitudinal tracking of hemocyte populations in vivo indicates lineage relationships and supports neural progenitor identity in adult neurogenesis

Adult neurogenesis, which takes place in both vertebrate and invertebrate species, is the process by which new neurons are born and integrated into existing functional neural circuits, long after embryonic development. Most studies in mammals suggest that self-renewing stem cells are the source of the new neurons, although the extent of self-renewal is a matter of debate. In contrast, research in the crayfish Procambarus clarkii has demonstrated that the neural progenitors producing adult-born neurons are capable of both self-renewing and consuming (non-self-renewing) divisions. However, self-renewing divisions are relatively rare, and therefore the production of adult-born neurons depends heavily on progenitors that are not replenishing themselves. Because the small pool of neural progenitors in the neurogenic niche is never exhausted throughout the long lives of these animals, we hypothesized that there must also be an extrinsic source of these cells. It was subsequently demonstrated that the neural progenitors originate in hemocytes (blood cells) produced by the immune system that travel in the circulation before ultimately integrating into niches where the neural lineage begins. The current study examines the developmental lineage of the three hemocyte types — hyaline (HC), semigranular (SGC) and granular (GC) cells — with the goal of understanding the origins of the progenitor cells that produce adult-born neurons. Longstanding qualitative metrics for hemocyte classification were validated quantitatively. Then, in a longitudinal study, proliferation markers were used to label the hemocytes in vivo, followed by sampling the circulating hemocyte population over the course of two months. Hemolymph samples were taken at intervals to track the frequencies of the different hemocyte types. These data reveal sequential peaks in the relative frequencies of HCs, SGCs and GCs, which were identified using qualitative and quantitative measures. These findings suggest that the three hemocyte types comprise a single cellular lineage that occurs in the circulation, with each type as a sequential progressive stage in hemocyte maturation beginning with HCs and ending with GCs. When combined with previously published data, this timeline provides additional evidence that HCs serve as the primary neural progenitor during adult neurogenesis in P. clarkii.

Disease characterization in cloned foals in Colombia, the effect of placental pathologies on the success and survival of cloned foalsfrom two different cell lines

Cloned foals born in the different cloning programs in the USA, Argentina, and recently in Colombia have experienced several pathological entities during their pregnancy and neonatal period. These entities include abortions, stillbirths, hypoxic-ischemic encephalopathy, large umbilical remanent, and angular deformity on the fore limb. The objectives of this study were to determine whether cloned foals suffer similar diseases and have the same mortality rate as noncloned ones and the differences between cloned foals from two different cell lines (fibroblastic and bone marrow cells) and, to establish whether mares carrying cloned foals from different cell lines have ultrasonographic, paraclinical, and hormonal profile parameters equal to traditional pregnancies and to determine whether there are differences between the cloned foals from the two different cell lines. In the analysis of the continuous variables, significant mean differences were established in the three groups of mares in PCV, hemoglobin, erythrocyte count, MCV, MCH, serum proteins and globulins, and in lymphocyte counts p<0.05. A risk analysis was made for morbidity and mortality associated with the cell origin of the clone and its pregnancy using chi-square sequential tests and logistic regression, and it was considered statistically significant at p< 0.05. A principal component analysis of the paraclinical findings of the mares with the outcome of the foal and the paraclinical parameters of the foals divided by the origin of gestation was performed to evaluate the components of the response variable and their dynamics. Thirty-four pregnancies of clones of fibroblastic origin, 26 of clones of bone marrow origin, and 32 of non-clones were studied. The presentation of placental diseases compatible with placentitis was significantly more frequent (p= 0.026) in mares with cloned foals from fibroblastic cell lines. Neonatal sepsis was determined to be the most frequent disease and was diagnosed more commonly in foals of fibroblastic cell origin—an increase in the risk (OR 37) (p=0.0006). The risk of death was positive and significant with the fibroblast cell line foals (OR: 9.1. P<0.01) compared to the cloned foals of marrow cell origin and non-cloned foals. The risk of death can be predicted in the neonatal period, and some indicators found in this study, such as signs related to placentitis, are associated with increased neonatal mortality and are more frequent in foals of fibroblastic cell origin.

Glia at Transition Zones.

Neural cells are segregated into their distinct central nervous system (CNS) and peripheral nervous system (PNS) domains. However, at specialized regions of the nervous system known as transition zones (TZs), glial cells from both the CNS and PNS are uniquely present with other specialized TZ cells. Herein we review the current understanding of vertebrate TZ cells. The article discusses the distinct cells at vertebrate TZs with a focus on cells that are located on the peripheral side of the spinal cord TZs. In addition to the developmental origin and differentiation of these TZ cells, the functional importance and the role of TZ cells in disease are highlighted. This article also reviews the common and unique features of vertebrate TZs from zebrafish to mice. We propose challenges and open questions in the field that could lead to exciting insights in the field of glial biology.

The Aquatic Symbiosis Genomics Project: probing the evolution of symbiosis across the Tree of Life

We present the Aquatic Symbiosis Genomics Project, a global collaboration to generate high quality genome sequences for a wide range of eukaryotes and their microbial symbionts. Launched under the Symbiosis in Aquatic Systems Initiative of the Gordon and Betty Moore Foundation, the ASG Project brings together researchers from across the globe who hope to use these reference genomes to augment and extend their analyses of the dynamics, mechanisms and environmental importance of symbioses. Applying large-scale, high-throughput sequencing and assembly technologies, the ASG collaboration will assemble and annotate the genomes of 500 symbiotic organisms – both the “hosts” and the microbial symbionts with which they associate. These data will be released openly to benefit all who work on symbioses, from conservation geneticists to those interested in the origin of the eukaryotic cell.

Localization and origins of juvenile skeletogenic cells in the sea urchin Lytechinuspictus

The development of the sea urchin larval body plan is well understood from extensive studies of embryonic patterning. However, fewer studies have investigated the late larval stages during which the unique pentaradial adult body plan develops. Previous work on late larval development highlights major tissue changes leading up to metamorphosis, but the location of specific cell types during juvenile development is less understood. Here, we improve on technical limitations by applying highly sensitive hybridization chain reaction fluorescent in situ hybridization (HCR-FISH) to the fast-developing and transparent sea urchin Lytechinus pictus, with a focus on skeletogenic cells. First, we show that HCR-FISH can be used in L. pictus to precisely localize skeletogenic cells in the rudiment. In doing so, we provide a detailed staging scheme for the appearance of skeletogenic cells around the rudiment prior to and during biomineralization and show that many skeletogenic cells unassociated with larval rods localize outside of the rudiment prior to localizing inside. Second, we show that downstream biomineralization genes have similar expression patterns during larval and juvenile skeletogenesis, suggesting some conservation of skeletogenic mechanisms during development between stages. Third, we find co-expression of blastocoelar and skeletogenic cell markers around juvenile skeleton located outside of the rudiment, which is consistent with data showing that cells from the non-skeletogenic mesoderm embryonic lineage contribute to the juvenile skeletogenic cell lineage. This work sets the foundation for subsequent studies of other cell types in the late larva of L. pictus to better understand juvenile body plan development, patterning, and evolution.

Genomic profiling in a subgroup analysis of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and extranodal (EN) sites of involvement in the phase 3 Pola-R-CHP versus R-CHOP (POLARIX) study.

7061 Background: The prognosis and survival outcomes of pts with EN involvement remain a challenge for DLBCL management. In the Phase 3 POLARIX study (NCT03274492), Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP in previously untreated DLBCL (Tilly et al. 2022). This retrospective analysis assessed clinical outcomes and genomic patterns of pts with DLBCL and EN disease. Methods: POLARIX methods were previously described (Tilly et al. 2022). Using a data cutoff of June 15, 2022, this analysis assessed pts with EN involvement as determined by investigators. Additional outcomes and genomics analyses were performed on pts whose EN status was confirmed from documented radiographic lesions or bone marrow biopsy with denotation of EN disease sites. Hazard ratios (HRs) for investigator-assessed PFS were adjusted for age (≤60 vs >60) and sex. Cell of origin (COO) by NanoString, mutation analysis by whole exome sequencing, and global gene expression profiling by RNAseq were performed centrally. Results: In POLARIX, 616/879 pts (70%) had identified EN involvement. After a median follow-up of 39.7 months, pts showed improved PFS with Pola-R-CHP vs R-CHOP (HR 0.72, 95% confidence interval [CI]: 0.55–0.96), with a 2-year PFS of 75% vs 66%. A total of 556 pts (Pola-R-CHP, n=279; R-CHOP, n=277) had confirmed sites of EN involvement, defined as pts with EN radiographic lesions or bone marrow disease. In these pts, PFS favored Pola-R-CHP vs R-CHOP but the difference was not statistically significant (HR 0.84, 95% CI: 0.63–1.13). Of pts with confirmed EN disease, 429 had COO results (activated B-cell, 145 [34%]; germinal center B-cell, 223 [52%]; unclassified DLBCL, 61 [14%]). Mutation data and frequencies of select clinically relevant mutations (Ptashkin, 2023) across EN sites were available for 364 pts (Table). Gene expression data were available for 418 pts; genes involved in proliferation (E2F or PI3K signaling targets and checkpoint genes) and regulated by IRF4, OCT2 and XBP1, were commonly upregulated in pts with EN disease. Conclusions: Results in pts with DLBCL with EN involvement suggest superior PFS with Pola-R-CHP vs R-CHOP. Ongoing analyses will further assess the independent impact of EN status on outcome. POLARIX represents the largest cohort of pts with annotated EN disease and systematic genomic analysis, providing new insights into the genomics of these pts. Clinical trial information: NCT03274492 . [Table: see text]

Dynamic reporters for probing real-time activation of human fibroblasts from single cells to populations.

Activation of fibroblasts is pivotal for wound healing; however, persistent activation leads to maladaptive processes and is a hallmark of fibrosis, where disease mechanisms are only partially understood. Human in vitro model systems complement in vivo animal models for both hypothesis testing and drug evaluation to improve the identification of therapeutics relevant to human disease. Despite advances, a challenge remains in understanding the dynamics of human fibroblast responses to complex microenvironment stimuli, motivating the need for more advanced tools to investigate fibrotic mechanisms. This work established approaches for assessing the temporal dynamics of these responses using genetically encoded fluorescent reporters of alpha smooth muscle actin expression, an indicator of fibroblast activation. Specifically, we created a toolset of human lung fibroblast reporter cell lines from different origins (male, female; healthy, idiopathic pulmonary fibrosis) and used three different versions of the reporter with the fluorescent protein modified to exhibit different temporal stabilities, providing temporal resolution of protein expression processes over a range of timescales. Using this toolset, we demonstrated that reporters provide insight into population shifts in response to both mechanical and biochemical cues that are not detectable by traditional end point assessments with differential responses based on cell origin. Furthermore, individual cells can also be tracked over time, with opportunities for comparison to complementary end point measurements. The establishment of this reporter toolset enables dynamic cell investigations that can be translated into more complex synthetic culture environments for elucidating disease mechanisms and evaluating therapeutics for lung fibrosis and other complex biological processes more broadly.

A Retrospective Study of R±DHAX Regimen versus R-CHOP Regimen First-Line Treatment of Elderly Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

To investigate the clinical efficacy and prognosis of Rituximab combined with DHAX and CHOP regimen in the first-line treatment of elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). A total of 36 elderly patients with DLBCL who were admitted and treated with 3 of more courses of treatment from August 2011 to August 2021 were retrospectively analyzed, and they were divided into rituximab±DHAX (R±DHAX) regimen group (18 cases) and rituximab±CHOP (R-CHOP) regimen group (18 cases) according to the treatment plan, and clinical features, efficacy and survival of the patients were observed. Compared with R-CHOP group, patients of the R±DHAX group were older, and had worse performance status and higher IPI score, the differences between two groups in age, ECOG score and IPI score were statistically significant ( P =0.005 P =0.018, P =0.035), but there were no significant differences beween two groups in gender, whether there were B symptoms, whether LDH was elevated, whether there was extranodal involvement, cell origin, bone marrow infiltration, and whether rituximab was combined ( P =0.738, P =1, P =0.315, P =0.305, P =0.413, P =0.177, P =0.711, P =0.229). The efficacy could be evaluated in 36 cases, including CR 14 (38.9%), PR 17 (47.2%), PD 5 (13.9%), and ORR of 86.1% (31/36). There were no statistically significant differences in CR［(27.8%（5/18） vs 50.0%（9/18）; P >0.05］ and PR ［44.4%（8/18） vs 50.0%（9/18）; P >0.05］ of R±DHAX group and R-CHOP group, there was statistically significant difference in ORR［72.2%（13/18） vs 100.0%（18/18）; P =0.045］ between two groups. The 1-year OS of R±DHAX group and R-CHOP group was (38.9±11.5%)% and (94.4±7.4%)%, respectively, 2-year OS was (16.7±8.8)% and (72.2±10.6)%, respectively, and the differences between two groups were statistically significant ( P =0.001, P =0.002). The median survival time in the R±DHAX group was 11 months(95%CI :8.9-13.1), and the median survival time in the R-CHOP group was not reached, and there was a statistically significant difference between the groups (P < 0.001). For elderly DLBCL patients, R±DHAX may not be superior to R-CHOP in OS, and ECOG score, IPI score and age may affect the survival of elderly DLBCL patients. However, R±DHAX regimen is safe, tolerable and has a certain efficacy, which can be used as one of the clinical treatment options for elderly DLBCL.

Whole exome sequencing analysis of intratumoral heterogeneity, tumor neoantigen burden and human leukocyte antigen loss of heterozygosity in HCC.

e16003 Background: Hepatocellular Carcinoma (HCC) patients has a high postoperative recurrence within 2 years and a low 5-year survival rate. However, molecular mechanisms for early recurrence are poorly understood. Immune checkpoint blockades (ICBs) show clinical benefits in HCC, with the immune microenvironment influencing ICBs therapeutic effects. Exploring the relationship between intratumoral heterogeneity (ITH), tumor neoantigen burden (TNB), and human leukocyte antigen loss of heterozygosity (HLA LOH) can deepen our understanding of the immune evasion mechanisms. Methods: In this study, whole exome sequencing (WES) was employed to analyze tumor specimens and matched peripheral blood controls derived from a cohort of 235 HCC patients. PD-L1 expression levels were assessed in the samples using immunohistochemistry. NetMHCpan was applied to predict neoantigen and quantified the peptide affinity of MHC-I genes measured by IC50. Neoantigen-MHC affinity was categorized as strong (IC50≤50nM), weak (50nM &lt; IC50≤500nM), and negative (IC50 &gt; 500nM). TNB was defined by the number of high affinity neoantigens per megabase in WES. Analysis of LOH was performed on HLA-I class genes and categorized as strong positive, weak positive, and negative groups. We used PyClone to conduct ITH analysis to assess the distribution of multiple subclones within a tumor. The average Cancer Cell Fraction (CCF) for each somatic mutation cluster was calculated, and these clusters were classified into major clones and subclones. Results: In 235 HCC samples, median TMB and TNB were 2.48 Muts/Mb and 0.30 Neos/Mb. Only 6.81% exhibited TMB-H (TMB≥10 Muts/Mb). TMB and TNB are significantly positively correlated (p &lt; 0.0001). HLA LOH occurred in 19.57% HCC patients, with high LOH samples having more high-affinity neoantigens (mean TNB 1.65 Neos/Mb). ITH analysis showed that 83.83% samples harbored subclonal clusters. HCC samples were divided into high (ITH≥0.908) and low (ITH &lt; 0.908) groups according to the median ITH of 0.908. High ITH group had higher TNB (median 0.43 vs 0.20 Neos/Mb) , more HLA LOH (9.24% vs 5.17% strong positive LOH). The high ITH groups exhibited a lower percentage of samples with elevated PD-L1 expression (14.29% vs 25.86%). The Combined Positive Score (CPS) revealed a significant difference between the groups (Fisher's test p = 0.03). Conclusions: In HCC, the high ITH group exhibited a higher proportion of HLA LOH compared to the low ITH group. Moreover, a decreased proportion of PD-L1 positive samples was observed in the high ITH group, suggesting that high ITH may be a key factor influencing treatment failure in immunotherapy. ITH analysis demonstrated a potential multi-subclonal origin of recurrent tumor cells, which is associated with immune escape, tumor malignancy,as well as the development of resistance.

Dual recombination-mediated genetic tracing reveals the origin of alveolar stem cells during lung repair and regeneration

Dual recombination-mediated genetic tracing reveals the origin of alveolar stem cells during lung repair and regeneration

Early Tapering of Cyclosporine Is Feasible in Haploidentical Stem Cell Transplantation: A Single Center Experience.

Cyclosporine-A (CsA) and post transplantation cyclophosphamide (PTCy) are common agents used for graft versus host disease (GVHD) prophylaxis in Haploidentical hematopoietic cell transplantation (haplo-HCT). However, the impact of CsA cessation timing in the posttransplant setting on clinical outcomes is uncertain. We aimed to investigate the impact of a novel approach that integrated early CsA cessation with PTCy utilization. This study was a single arm retrospective study carried out at a tertiary referral hospital hematology and bone marrow transplantation center between 2009 and 2022. The patients who received haplo-HCT with ATG, PTCy and CsA as GVHD prophylaxis were included. CsA was planned for cessation starting at day 45 to day 60. Acute and chronic GVHD were evaluated and graded. CsA blood concentrations and its impact on acute and chronic GVHD was evaluated. Thirty-one patients composed of 19 (61.3%) male and 12 (38.7%) female patients with a median age of 31 years (20-58). Busulfan and TBI based conditioning regimens were the most utilized regimens. The majority of donors were first degree relatives. Stem cell origin was peripheral blood for all patients. GVHD prophylaxis consisted of ATG, CsA and PTCy. Acute GVHD was observed in 9 (29%) cases, whereas chronic GVHD was seen in 3 (9.7%) cases, with 2 of them having overlapping GVHD. Age, gender, number of chemotherapy lines, transplant characteristics, infused CD34 cell count, and engraftment durations were similar among patients with and without GVHD. Patients with GVHD had similar 1st, 2nd, 3rd and 4th week CsA concentrations compared to patients without GVHD (p>0.05). The presence of GVHD was not associated with worse progression free survival and overall survival (p=0.6, p=0.5, respectively). CMV reactivation was more common in the GVHD group. In the current study, we did not find an impact of CsA concentration on GVHD and post-transplant outcomes in Haplo-HCT setting. Therefore, together with the use of PTCy, early CsA cessation can be an option; further studies are needed to understand all aspects of this approach.

Increased risk for thyroid carcinoma in patients with Li-Fraumeni syndrome.

10612 Background: Patients with Li-Fraumeni syndrome (LFS) are predisposed to a 90% lifetime risk of cancer, thus undergoing extensive cancer surveillance. While thyroid cancer is not a core LFS-associated malignancy, increased incidence of thyroid carcinoma has been reported within the LFS tumor spectrum. In the general population, thyroid cancer incidence has soared mainly via incidental detection. We investigated the rate of thyroid carcinoma in relation to p53 mutational process and increased screening. Methods: A retrospective chart review was conducted for clinico-pathological features for adult carriers of confirmed germline TP53 variants at three tertiary cancer centers. Standardized incidence ratio (SIR) was calculated using age, sex, and year-specific expected incidence rates of thyroid cancer from Surveillance, Epidemiology, and End Results (SEER) 1975 – 2020 data. Results: Among 600 patients from 400 families with LFS, 39 (6.5%) patients from 36 (9%) families developed thyroid carcinoma at an average age of 42 years (median = 40, ranged from 23 to 70 years of age). The majority of LFS patients with thyroid carcinoma were female (N=30, 77%). Thyroid carcinoma was the presenting cancer diagnosis in 17 (44%) patients. Over 70% of thyroid carcinoma diagnoses (N=31) were detected incidentally either via LFS cancer screening (N=12, 39%) or via an imaging study unrelated to LFS screening (N=10, 32%). All 39 thyroid carcinomas were of follicular cell origin (non-medullary), most were multifocal (67% of N=32), and 30% had nodal metastasis (N=10 of 33). Of 35 tumors with histologic data, papillary carcinoma (papillary, follicular, and tall cell subtypes) was most common (N=29, 83%), followed by follicular carcinoma (N=4, 11%) and oncocytic carcinoma (N=2, 6%). LFS patients most often underwent a total thyroidectomy (N=27, 69%) compared to a hemithyroidectomy (N=10, 26%) or hemithyroidectomy with completion surgery within three months (N=2, 5%). Intermediate to high risk of recurrence based on tumor characteristics was noted in 17 patients (44%), warranting consideration of radioactive iodine (RAI) therapy, including tall cell subtype (N=3), oncocytic or follicular histology, incomplete resection (N=2), extrathyroidal extension (N = 6), and greater than five positive lymph nodes (N=6). Five (29%) of these 17 patients received RAI. The SIR for thyroid carcinoma in LFS compared to SEER was 13 (95% CI 9.2-17.8, p&lt;0.0001). The SIR was elevated for LFS patients diagnosed with thyroid carcinoma both prior to and after genetic testing (SIR 9.0, CI 5.3-14.2, p&lt;0.0001 and SIR 20, CI 12.2- 30.9, p&lt;0.0001, respectively). Conclusions: In this multi-institutional cohort, a 6-9% prevalence rate of thyroid carcinoma was observed in LFS patients and families, with &gt;70% of the tumors identified incidentally. The rate of thyroid carcinoma in LFS is significantly elevated over the general population.

CAR-T Therapy in Multiple Myeloma: Looking Beyond

Multiple Myeloma is a hematological neoplasm that, over the recent few years, has benefited from numerous therapeutic options. Among the latter, CAR-T stands out as the most recent and one of the most promising treatments currently available. Despite its recent introduction, multiple CAR-T products have already been approved, and research regarding cellular therapy is rapidly increasing. We conducted a comprehensive search and review of the available literature, including published studies and abstracts from recent meetings (ASH, ASCO, ASTCT, IMS), regarding Multiple Myeloma and CAR-T therapy. We describe the discovery and research regarding promising targets like the B-Cell Maturation Antigen (BCMA) and others, the origin and nature of CAR-T cells, and the recent introduction of anti-BCMA CAR-Ts Idecabtagene-vicleucel and Ciltacabtagene-autoleucel, which are currently the only approved CAR-T products for MM. Additionally, we discuss non-BCMA-targeting CAR-Ts and their clinical implications. Given the significant impact of cellular therapy, we provide an overview of its limitations and possible adverse implications, as well as related resistance mechanisms. Finally, we describe the current research aimed at improving CAR-T therapy in MM, including structural innovations and new therapeutic approaches, such as in the earlier lines of treatment and maintenance therapy.