Objective: Early death (ED) characteristics and predictive factors analysis in patients with severe/very severe aplastic anemia (SAA/VSAA) treated with intensive immunosuppression therapy and establish an ED prediction model. Methods: The clinical data of 232 patients with SAA/VSAA treated with Antithymocyte immunoglobulin (ATG) at the Peking Union Medical College Hospital from August 2003 to August 2021 were collected. The characteristics and causes of ED within 90 days were analyzed retrospectively. Cox proportional hazards model was used to screen the ED risk factors and build a prediction model. Results: Only 19 patients (8.2% ) developed ED with a median time of 24 (3-85) days among the 232 patients with SAA/VSAA who received ATG treatment. The main cause of ED was infection (84.2% ) , followed by cerebral hemorrhage (10.5% ) . Multivariate analysis showed that VSAA (HR=15.359, 95% CI 1.935-121.899, P=0.010) , fungal infection prevention by posaconazole (HR=0.147, 95% CI 0.019-1.133, P=0.066) , lymphocyte count (LYM) ≤ 0.5×10(9)/L (HR=3.386, 95% CI 1.123-10.206, P=0.030) , and PLT ≤ 5×10(9)/L (HR=8.939, 95% CI 1.948-41.019, P=0.005) were ED's independent influencing factors. To build a clinical prediction model, VSAA, fungal infection prevention by posaconazole, LYM ≤ 0.5×10(9)/L, and PLT ≤ 5×10(9)/L were scored with 3, -2, 1, and 2, respectively. The integral model AUC=89.324 (95% CI 80.859-97.789) . The ED risk in patients with a score ≥ 3 was 23.1 (95% CI 5.3-100.2) times that in patients with a score<3. Conclusion: ED caused by infection and cerebral hemorrhage is an important challenge for SAA/VSAA to be treated with ATG. VSAA, LYM ≤ 0.5×10(9)/L, and PLT ≤ 5×10(9)/L patients who did not use posaconazole to prevent fungal infection had a high ED risk.

Objective: To investigate how gender differences between the donor and the recipient affect the effectiveness of antithymocyte globulin (ATG) and pure peripheral blood stem cell (PBSC) hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of malignant hematological diseases. Methods: From February 2015 to September 2020, 648 hematological malignancies patients underwent myeloablative condition regimen haplo-HSCT treatment at the Bone Marrow Transplant Center of the First Affiliated Hospital of Zhejiang University. The median age was 32 (14-62) years, with 363 males (56.0% ) and 285 females (44.0% ) present. 242 cases of acute lymphoblastic leukemia (ALL) (37.3% ) , 293 cases of acute myeloid leukemia (AML) (45.2% ) , 56 cases of myelodysplastic syndrome (MDS) (8.7% ) , 27 cases of non-Hodgkin's lymphoma (NHL) (4.2% ) , and 30 cases of other hematological malignancies (4.6% ) . Results: ① The 3-year overall survival (OS) , DFS, the incidence of Ⅱ-Ⅳ grade acute graft-versus-host disease (aGVHD) , the incidence of Ⅲ-Ⅳ grade aGVHD, the 3-year incidence of moderate & severe chronic GVHD (cGVHD) , severe cGVHD, the 3-year incidence of relapse, and NRM of the whole group were (73.10±1.90) % , (70.80±1.90) % , (33.96±1.87) % , (13.08±1.33) % , (35.10±2.14) % , (10.66±1.38) % , (19.43±1.67) % , and (9.80±1.24) % , respectively. ②There was no statistically significant difference between the donor-recipient gender match and donor-recipient gender mismatch groups in the 28-day cumulative neutrophil engraftment rate, 28-day cumulative platelet engraftment rate, the incidence of Ⅱ-Ⅳ grade aGVHD, the incidence of Ⅲ-Ⅳ grade aGVHD, 3-year OS, 3-year DFS, the cumulative incidence of relapse, NRM, and incidence of moderate & severe cGVHD, severe cGVHD. ③The 28-day cumulative neutrophil engraftment rate did not differ statistically between the male-female, female-female, male-male, and female-male groups (P=0.148) . The incidence of Ⅱ-Ⅳ grade aGVHD, the incidence of Ⅲ-Ⅳ grade aGVHD, 3-year OS, 3-year DFS, cumulative relapse rate, and NRM, and the incidence of cGVHD were not statistically different among the four groups (P>0.05) . The 28-day cumulative platelet engraftment rate of the female-male group was significantly lower than male-female group, and the female-female group [ (91.45±2.63) % vs. (94.77±1.75) % , P=0.004; (91.45±2.63) % vs. (95.54±2.05) % , P=0.005]. No significant difference existed in the 28-day cumulative platelet engraftment rate between the female-male group and the male-male group [ (91.45±2.63) % vs. (95.08±1.41) % , P=0.284]. ④Among patients ≤35 years old, the 3-year incidence of severe cGVHD patients receiving sister donors and sibling donors were (26.71±5.90) % and (10.33±4.43) % , respectively (P=0.054) . Patients accepting daughter donors and son donors had a 3-year incidence of moderate and severe cGVHD that was 40.07% vs. 27.41% , respectively, among those over 35 (40.07±6.65) % vs. (27.41±4.54) % (P=0.084) . ⑤Female donors to male recipients had a significantly lower 28-day cumulative platelet engraftment rate compared to the other groups [ (91.45±2.63) % vs. (95.08±0.95) % , P=0.037]. ⑥ Female donors to male recipients had a significantly lower 28-day cumulative platelet engraftment rate than the other groups in the ATG-Fresenius (ATG-F) 10 mg/kg group [ (89.29±4.29) % vs. (94.49±1.45) % , P=0.037]. But when compared to the other groups in the Rabbit Antihuman Thymocyte Immunoglobulin (rATG-T) 6 mg/kg group, the 28-day cumulative platelet implantation rate between female donors and male recipients was not significantly different [ (93.44±3.38) % vs. (95.62±1.26) % , P=0.404]. Conclusion: The main clinical outcomes of patients with malignant blood diseases following transplantation are unaffected by the gender combination of the donor and patient in the haplo-HSCT mode based on ATG and PBSC sources. Female donors to male recipients have a lower 28-day cumulative platelet engraftment rate and longer platelet engraftment times.

Rhino-orbital cerebral mucormycosis has been commonly seen during the coronavirus disease 2019 (COVID-19) pandemic. Several factors responsible for etiology and pathophysiology have been identified, among which corticosteroids and diabetes have contributed to the lion's share of the outbreak of mucormycosis. In this report, we discuss a case of a 41-year-old non-diabetic male with a recent convalescence from COVID-19 infection presented with gradual vision loss and loss of sensations in his right eye. He was found to have periorbital swelling, restriction of extraocular movements in all gazes, chemosis, ptosis of the right eye, and right maxillary sinus tenderness. His serum investigations, radiologic findings, and blood culture were indicative of rhino-orbital cerebral mucormycosis. He was started on systemic liposomal amphotericin B immediately and underwent aggressive surgical debridement. A high index of clinical suspicion, aggressive multifaceted management, and follow-up are needed to have successful outcomes, thereby lowering the morbidity of coronavirus-associated mucormycosis.

KDM5B histone demethylase is overexpressed in many cancers and plays an ambivalent role in oncogenesis, depending on the specific context. This ambivalence could be explained by the expression of KDM5B protein isoforms with diverse functional roles, which could be present at different levels in various cancer cell lines. We show here that one of these isoforms, namely KDM5B-NTT, accumulates in breast cancer cell lines due to remarkable protein stability relative to the canonical PLU-1 isoform, which shows a much faster turnover. This isoform is the truncated and catalytically inactive product of an mRNA with a transcription start site downstream of the PLU-1 isoform, and the consequent usage of an alternative ATG for translation initiation. It also differs from the PLU-1 transcript in the inclusion of an additional exon (exon-6), previously attributed to other putative isoforms. Overexpression of this isoform in MCF7 cells leads to an increase in bulk H3K4 methylation and induces derepression of a gene cluster, including the tumor suppressor Cav1 and several genes involved in the interferon-alpha and -gamma response. We discuss the relevance of this finding considering the hypothesis that KDM5B may possess regulatory roles independent of its catalytic activity.

Reducing the recipient's T cell repertoire is considered to increase the efficacy of regulatory T cell (Treg) therapy. This necessitates timing the administration of antithymocyte globulin (ATG) early enough before adoptive cell therapy (ACT) so that residual serum ATG does not deplete the transferred Tregs. The optimum time point in this regard has not been defined. Herein, we report the effects of residual serum ATG on the viability of an in vitro expanded Treg cell product used in a clinical trial of ACT in kidney transplant recipients (NCT03867617). Patients received ATG monotherapy (either 6 or 3 mg/kg body weight) without concomitant immunosuppression 2 to 3 weeks before transplantation and Treg transfer. An anti-ATG immunoglobulin G (IgG) immune response was elicited in all patients within 14 days. In turn, the elimination of total and Treg-specific ATG was accelerated substantially over control patients receiving the same dose of ATG with concomitant immunosuppression. However, ATG serum concentrations of <1 μg/mL, which had previously been reported as subtherapeutic threshold, triggered apoptosis of Tregs in vitro. Therefore, ATG levels need to decline to lower levels than those previously thought for efficacious Treg transfer. In 5 of 6 patients, such low levels of serum ATG considered safe for Treg transfer were reached within 2 weeks after ATG administration.

Introduction: Saethre-Chotzen syndrome, a craniosynostosis syndrome characterized by the premature closure of the coronal sutures, dysmorphic facial features and limb anomalies, is caused by haploinsufficiency of TWIST1. Although the majority of variants localize in the coding region of the gene, two variants in the 5' UTR have been recently reported to generate novel upstream initiation codons. Methods: Skeletal dysplasia Next-generation sequencing (NGS) panel was used for genetic analysis in a patient with bicoronal synostosis, facial dysmorphisms and limb anomalies. The variant pathogenicity was assessed by a luciferase reporter promoter assay. Results: Here, we describe the identification of a third ATG-creating de novo variant, c.-18C>T, in the 5' UTR of TWIST1 in the patient with a clinical diagnosis of Saethre-Chotzen syndrome. It was predicted to create an out-of-frame new upstream translation initiation codon resulting in a 40 amino acid larger functionally inactive protein. We performed luciferase reporter promoter assays to demonstrate that the variant does indeed reduce translation from the main open reading frame. Conclusion: This is the third variant identified in this region and confirms the introduction of upstream ATGs in the 5' UTR of TWIST1 as a pathogenic mechanism in Saethre-Chotzen syndrome. This case report shows the necessity for performing functional characterization of variants of unknown significance within national health services.

The use of anti-thymocyte globulin (ATG) as part of conditioning to prevent graft-versus-host disease (GVHD) may severely impair immune reconstitution (IR). We analyzed relationships between ATG exposure, the recipient lymphocyte count, IR, and transplant outcome. We retrospectively reviewed patients aged ≤ 18 years who underwent allogeneic HSCT between April 2005 and April 2020. The outcomes of interest included the incidence of GVHD, overall survival (OS), and IR. IR was analyzed through thymic magnetic resonance imaging (MRI) and by quantifying T CD4+ and recent thymic emigrants (RTEs). The ATG-exposed group was split into a low ATG/lymphocyte ratio subgroup (ratio < 0.01) and a high ATG/lymphocyte ratio subgroup (ratio > 0.01). The low ratio subgroup had a higher incidence of GVHD (29 [59%] vs. 7 [16.6%]) but a better IR in both laboratory and MRI imaging assessments (p < 0.0001). The median thymic volume in the low ratio subgroup was significantly higher (14.7 cm3 vs. 4.5 cm3, p < 0.001). This was associated with a better OS and lower transplant-related mortality (TRM) (80.4% vs. 58.0%, p = 0.031) and (13.1% vs. 33.0%, p = 0.035). An individualized approach to ATG dosing allows for the obtainment of rapid thymic reconstitution and the best transplant-related outcomes.

Vacuolar processing enzymes (VPEs) are plant cysteine proteases that are subjected to autoactivation in an acidic pH. It is presumed that VPEs, by activating other vacuolar hydrolases, are in control of tonoplast rupture during programmed cell death (PCD). Involvement of VPEs has been indicated in various types of plant PCD related to development, senescence, and environmental stress responses. Another pathway induced during such processes is autophagy, which leads to the degradation of cellular components and metabolite salvage, and it is presumed that VPEs may be involved in the degradation of autophagic bodies during plant autophagy. As both PCD and autophagy occur under similar conditions, research on the relationship between them is needed, and VPEs, as key vacuolar proteases, seem to be an important factor to consider. They may even constitute a potential point of crosstalk between cell death and autophagy in plant cells. This review describes new insights into the role of VPEs in plant PCD, with an emphasis on evidence and hypotheses on the interconnections between autophagy and cell death, and indicates several new research opportunities.

In the last decade, the phylogenetic relationships within the genus Triplophysa have become controversial, due to a lack of molecular data. The mitochondrial genome plays a vital role in the reconstruction of phylogenetic relationships and in revealing the molecular evolution of bony fishes. Herein, we obtained the complete mitogenome of Triplophysa bombifrons via HiFi reads of the Pacbio Sequel II system and DNBSEQ short-reads. We compared all available mitogenomes of the Triplophysa genus and reconstructed the phylogeny of Nemacheilidae, based on the mitogenomes, using maximum likelihood (ML) methods. The results show that the complete mitogenome sequence of T. bombifrons was circular and 16,568 bp in length, including 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA), 2 ribosomal RNA (rRNA), and a typical control region (D-loop). The most common start codons were ATG, except for cox1, and TAA/TAG were the stop codons for all PCGs. In total, 677 SNPs and 9 INDELs have been found by comparing the sequence divergence between this study and previous reports. Purity selection was found in all PCGs. Phylogeny was inferred by analyzing the 13 PCGs and the concatenated nucleotide sequences of 30 mitogenomes. The phylogenetic analyses based on the nucleotides of the 13 PCGs supported the assumption that the Triplophysa genus can be divided into 4 main clades and demonstrated that T. bombifrons and T. tenuis are closely related species for the first time. This study laid the foundation for further study on the mitogenome and phylogeny of Nemacheilidae fishes.

There are limited data on second stem cell transplantation (SCT2) outcomes with alternative donors for relapsed AML after the first stem cell transplantation (SCT1). We analyzed the outcomes of 52 adult AML patients who received SCT2 from haploidentical donors (HIT, N = 32) and double-cord blood (dCBT, N = 20) between 2008 and 2021. The HIT group received T-cell-replete peripheral blood stem cells after reduced-toxicity conditioning with anti-thymocyte globulin (ATG), while the dCBT group received myeloablative conditioning. For a median follow-up of 64.9 months, the HIT group, compared to the dCBT group, had earlier engraftment, superior 2-year overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) with similar relapse. Multivariate analysis demonstrated that HIT was significantly associated with better OS, DFS, and lower NRM than dCBT. Both longer remission duration after SCT1 and complete remission at SCT2 were significantly associated with a lower relapse rate. In addition, bone marrow WT1 measurable residual disease (MRD) positivity was significantly associated with inferior OS and higher relapse. This study suggests that T-cell-replete HIT with ATG-based GVHD prophylaxis may be preferred over dCBT as SCT2 for relapsed AML and that WT1-MRD negativity may be warranted for better SCT2 outcomes.

Strategies to minimize immune-suppressive medications after liver transplantation are limited by allograft rejection. Biopsy of liver is the current standard of care in diagnosing rejection. However, it adds to physical and economic burden to the patient and has diagnostic limitations. In this review, we aim to highlight the different biomarkers to predict and diagnose acute rejection. We also aim to explore recent advances in molecular diagnostics to improve the diagnostic yield of liver biopsies.

Eltrombopag (EPAG) can improve the efficacy of immunosuppressive therapy (IST) consisting of antithymocyte immunoglobulin (ATG) and cyclosporin in severe aplastic anemia (SAA) patients. This study explored whether patients with SAA could benefit from continuous usage of EPAG beyond 6 months.Seventy-four treatment-naive Chinese patients with SAA were administrated with rabbit ATG-based IST plus EPAG for 6 months. Patients not achieving complete remission (CR) at 6 months were treated with EPAG for another 6 months.At 1, 3, 6 and 12 months after IST, the cumulative response rates were 31%, 61%, 82% and 90%, and the cumulative CR rates were 0, 14%, 27% and 45%, respectively. The cumulative effect curve showed that 93% and 53% of all remission and CR occurred within 6 months, while 98% and 83% of all remission and CR occurred within 12 months. Thirty-seven percent of patients (11 of 30) with partial remission (PR) at 6 months continuously exposed to EPAG improved to CR within 3 (1-5) months of the extended median time. Six patients failing at 6 months continued to use EPAG. Three patients showed improved responses with an extended median time of 6 (1-6) months. The 2-year event-free survival (EFS) was better in those continuing with EPAG (89% vs. 49%, P = 0.006) for patients with PR or non-remission at 6 months.Continuous administration with EPAG could improve the hematologic response and EFS in patients without achieving CR at 6 months.This trial has been registered at the Chinese Clinical Trial Registry (ChiCTR2100045895).

Nanotechnology is a growing field, with many potential biomedical applications of nanomedicine for the treatment of different diseases, particularly cancer, on the horizon. Graphene oxide (GO) nanoparticles can act as carbon-based nanocarriers with advantages such as a large surface area, good mechanical strength, and the capacity for surface modification. These nanostructures have been extensively used in cancer therapy for drug and gene delivery, photothermal therapy, overcoming chemotherapy resistance, and for imaging procedures. In the current review, we focus on the biological functions of GO nanoparticles as regulators of apoptosis and autophagy, the two major forms of programmed cell death. GO nanoparticles can either induce or inhibit autophagy in cancer cells, depending on the conditions. By stimulating autophagy, GO nanocarriers can promote the sensitivity of cancer cells to chemotherapy. However, by impairing autophagy flux, GO nanoparticles can reduce cell survival and enhance inflammation. Similarly, GO nanomaterials can increase ROS production and induce DNA damage, thereby sensitizing cancer cells to apoptosis. In vitro and in vivo experiments have investigated whether GO nanomaterials show any toxicity in major body organs, such as the brain, liver, spleen, and heart. Molecular pathways, such as ATG, MAPK, JNK, and Akt, can be regulated by GO nanomaterials, leading to effects on autophagy and apoptosis. These topics are discussed in this review to shed some lights towards the biomedical potential of GO nanoparticles and their biocompatibility, paving the way for their future application in clinical trials.

Acquired aplastic anemia (AA) is a bone marrow failure disorder characterized by pancytopenia, and immunosuppressive therapy (IST) is the optional first-line management. Several studies identified the influencing factors on IST response; however, there are still a considerable number of patients suffering from poor prognoses. In this study, we enrolled 61 AA patients aged ≤ 40 years old, and whole-exome sequencing (WES) found unexpected high FANC heterozygous germline mutations (28/61, 45.9%). Patients with FANC mutations have a significantly lower absolute reticulocyte count and CD34+ % in the bone marrow and also lower 3-, 6-, and 9-month IST response than that without mutation, which were 0% vs. 25% (P = 0.017), 26.3% vs. 42.1% (P = 0.495), and 29.4% vs. 72.2% (P = 0.011), especially in anti-thymocyte globulin combined with the cyclosporin A (ATG + CsA) group, which were 0% vs.33.4% (P = 0.143), 25% vs.83.3% (P = 0.103), and 25% vs. 100% (P = 0.003), respectively. The event-free survival in the FANCwt group was also better than that in the FANCmut group (P = 0.016) and also showed in patients who received ATG + CsA treatment (P = 0.045). In addition, all the adverse effects of FANC germline mutation were not significant in stem cell-transplanted group. Our result indicated that the WES-based detection of FANC heterozygous germline mutations may have a great meaning in predicting IST response of acquired AA. This study was registered at chictr.org.cn (# ChiCTR2100054992).

Objective To investigate the expression regulation of autophagy-related genes(ATG)and the mechanism of autophagy in rheumatoid arthritis(RA).Methods The differentially expressed genes(DEG)of RA were identified from GSE55235 and GSE55457,on the basis of which the differentially expressed autophagy-related genes(DE-ATG)were selected from the Human Autophagy Database.STRING 11.0 and GeneMANIA were used to establish protein-protein interaction networks.Further,the transcription factor-gene-miRNA co-expression network was established via NetworkAnalyst and Cytoscape.Finally,receiver operating characteristic(ROC)curve and DrugBank were employed to evaluate the efficacy of the predicted biomarkers and the performance of drugs targeting DE-ATG.GraphPad Prism 8.2.1 and R 4.0.3 were used for statistical analysis and graphics.Results A total of 485 DEG were enriched in signaling pathways such as T cell activation,hormone regulation,osteoclast differentiation,RA,and chemokines.Eleven DE-ATG regulated the expression of RUNX1,TP53,SOX2,and hsa-mir-155-5p in synovial tissues of RA patients and were involved in the response to environmental factors such as 2,3,7,8-tetrachlorodibenzodioxin and silicon dioxide.The ROC curve analysis identified the DE-ATG with good sensitivity and specificity,such as MYC,MAPK8,CDKN1A,and TNFSF10,which can be used to distinguish certain phenotypes and serve as novel biomarkers for RA.Conclusions In RA,down-regulated DE-ATG expression may promote apoptosis and lysis of chondrocytes.The identified novel biomarkers provides new ideas and methods for diagnosing and treating RA.The establishment of transcription factor-miRNA-gene co-expression network provides direct evidence for dissecting synovial inflammation and articular cartilage destruction.

In the search for solution-processable TADF materials as a light emitting layer for OLED devices, polymers have attracted considerable attention due to their better thermal and morphological properties in the film state with respect to small molecules. In this work, a new polymer (p-TPS-DMAC-TRZ) with thermally activated delayed fluorescence (TADF) light-emitting characteristics was prepared from a conjugation-break unit (TPS) and a well-known TADF core (DAMC-TRZ). This material was designed to preserve the photophysical properties of DAMC-TRZ, while improving other properties, such as thermal stability, promoted by its polymerization with a TPS core. Along with excellent solubility in common organic solvents such as toluene, chloroform and THF, the polymer (Mn = 9500; Mw = 15200) showed high thermal stability (TDT5% = 481 °C), and a Tg value of 265 °C, parameters higher than the reference small molecule DMAC-TRZ (TDT5% = 305 °C; Tg = 91 °C). The photoluminescence maximum of the polymer was centered at 508 nm in the solid state, showing a low redshift compared to DMAC-TRZ (500 nm), while also showing a redshift in solution with solvents of increasing polarity. Time-resolved photoluminescence of p-TPS-DMAC-TRZ at 298 K, showed considerable delayed emission in solid state, with two relatively long lifetimes, 0.290 s (0.14) and 2.06 s (0.50), and a short lifetime of 23.6 ns, while at 77 K, the delayed emission was considerably quenched, and two lifetimes in total were observed, 24.6 ns (0.80) and 180 ns (0.20), which was expected from the slower RISC process at lower temperatures, decreasing the efficiency of the delayed emission and demonstrating that p-TPS-DMAC-TRZ has a TADF emission. This is in agreement with room temperature TRPL measurements in solution, where a decrease in both lifetime and delayed contribution to total photoluminescence was observed when oxygen was present. The PLQY of the mCP blend films with 1% p-TPS-DMAC-DMAC-TRZ as a dopant was determined to be equal to 0.62, while in the pure film, it was equal to 0.29, which is lower than that observed for DMAC-TRZ (0.81). Cyclic voltammetry experiments showed similarities between p-TPS-DMAC-TRZ and DAMC-TRZ with HOMO and LUMO energies of -5.14 eV and -2.76 eV, respectively, establishing an electrochemical bandgap value of 2.38 eV. The thin film morphology of p-TPS-DMAC-TRZ and DMAC-TRZ was compared by AFM and FE-SEM, and the results showed that p-TPS-DMAC-TRZ has a smoother surface with fewer defects, such as aggregations. These results show that the design strategy succeeded in improving the thermal and morphological properties in the polymeric material compared to the reference small molecule, while the photophysical properties were mostly maintained, except for the PLQY determined in the pure films. Still, these results show that p-TPS-DMAC-TRZ is a good candidate for use as a light-emitting layer in OLED devices, especially when used as a host-guest mixture in suitable materials such as mCP.

Autophagy is a fundamental multi-tasking adaptive cellular degradation and recycling strategy. Following its causal implication in age-related decline, autophagy is currently among the most broadly studied and challenged mechanisms within aging research. Thanks to these efforts, new cellular nodes interconnected with this phylogenetically ancestral pathway and unexpected roles of autophagy-associated genetic products are unveiled daily, yet the history of functional adaptations of autophagy along its evolutive trail is poorly understood and documented. Autophagy is traditionally studied in canonical and research-wise convenient model organisms such as yeast and mice. However, unconventional animal models endowed with extended longevity and exemption from age-related diseases offer a privileged perspective to inquire into the role of autophagy in the evolution of longevity. In this mini review we retrace the appearance and functions evolved by autophagy in eukaryotic cells and its protective contribution in the pathophysiology of aging.

Adequate mass and function of adipose tissues (ATs) play essential roles in preventing metabolic perturbations. The pathological reduction of ATs in lipodystrophy leads to an array of metabolic diseases. Understanding the underlying mechanisms may benefit the development of effective therapies. Several cellular processes, including autophagy and vesicle trafficking, function collectively to maintain AT homeostasis. Here, we investigated the impact of adipocyte-specific deletion of the lipid kinase phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) on AT homeostasis and systemic metabolism in mice. We report that PIK3C3 functions in all ATs and that its absence disturbs adipocyte autophagy and hinders adipocyte differentiation, survival, and function with differential effects on brown and white ATs. These abnormalities cause loss of white ATs, whitening followed by loss of brown ATs, and impaired "browning" of white ATs. Consequently, mice exhibit compromised thermogenic capacity and develop dyslipidemia, hepatic steatosis, insulin resistance, and type 2 diabetes. While these effects of PIK3C3 largely contrast previous findings with the autophagy-related (ATG) protein ATG7 in adipocytes, mice with a combined deficiency in both factors reveal a dominant role of the PIK3C3-deficient phenotype. We have also found that dietary lipid excess exacerbates AT pathologies caused by PIK3C3 deficiency. Surprisingly, glucose tolerance is spared in adipocyte-specific PIK3C3-deficient mice, a phenotype that is more evident during dietary lipid excess. These findings reveal a crucial yet complex role for PIK3C3 in ATs, with potential therapeutic implications.

Allogenic hematopoietic cell transplantation (HCT) is the best curative approach for patients with severe aplastic anemia (SAA). The outcomes of HCT from haploidentical family donors (HFDs) have improved, making it a feasible option for patients lacking an HLA-identical donor. However, data on HFD-HCT for younger patients with SAA is sparse. In this multicenter retrospective study, we evaluated the outcomes of 79 patients undergoing HFD-HCT for SAA. All the patients were heavily pretransfused, the median time to HCT was >12 months, and 67% had failed previous therapies. Conditioning was based on fludarabine (Flu)-cyclophosphamide (Cy)-antithymocyte globulin (ATG)/total body irradiation (TBI) with or without thiotepa/melphalan (TT/Mel). Post-transplantation Cy (PTCy) and calcineurin inhibitors (CNIs)/sirolimus were used as graft-versus-host disease (GVHD) prophylaxis with or without abatacept. The rate of primary graft failure (PGF) was 16.43% overall, lower in patients conditioned with TT/Mel. The incidences of acute and chronic GVHD were 26.4% and 18.9%, respectively. At a median follow-up of 48 months, the overall survival (OS) and event-free survival (EFS) were 61.6% and 58.1%, respectively. Both OS and EFS were better in the TT/Mel recipients and with abatacept as GVHD prophylaxis. On multivariate analysis, the use of abatacept was found to favorably impact the outcome variables, including GVHD and EFS. Our study suggests that PTCy-based HFD-HCT is a reasonable option for young patients with high-risk SAA, in whom optimization of conditioning and GVHD prophylaxis might further improve outcomes.