[Severe aplastic anemia exhibiting mild COVID-19 despite high serum IL-6 levels].

COVID-19 is a viral infection characterized by a cytokine storm similar to that in acute respiratory distress syndrome (ARDS). Neutrophils and monocytes are known to play an important role in tissue damage in ARDS. COVID-19 has been reported to be more severe in patients with hematological malignancies; however, there are few reports of COVID-19 in patients with aplastic anemia. Moreover, how aplastic anemia affects COVID-19 remains unclear. Here, we report the case of a COVID-19 patient with aplastic anemia who had high serum IL-6 levels but did not progress to the severe form of COVID-19. We inferred that severe neutropenia and monocytopenia due to aplastic anemia could contribute to a mild form of COVID-19, although a risk of more severe secondary bacterial infections exists.

Role of allograft inflammatory factor-1 in bleomycin-induced lung fibrosis.

Allograft inflammatory factor-1 (AIF-1) is a protein expressed by macrophages infiltrating the area around the coronary arteries in a rat ectopic cardiac allograft model. We previously reported that AIF-1 is associated with the pathogenesis of rheumatoid arthritis and skin fibrosis in sclerodermatous graft-versus-host disease mice. Here, we used an animal model of bleomycin-induced lung fibrosis to analyze the expression of AIF-1 and examine its function in lung fibrosis. The results showed that AIF-1 was expressed on lung tissues, specifically macrophages, from mice with bleomycin-induced lung fibrosis. Recombinant AIF-1 increased the production of TGF-ß which plays crucial roles in the mechanism of fibrosis by mouse macrophage cell line RAW264.7. Recombinant AIF-1 also increased both the proliferation and migration of lung fibroblasts compared with control group. These results suggest that AIF-1 plays an important role in the mechanism underlying lung fibrosis, and may provide an attractive new therapeutic target.

Inhibition of osteoclastogenesis by osteoblast-like cells genetically engineered to produce interleukin-10.

Bone destruction at inflamed joints is an important complication associated with rheumatoid arthritis (RA). Interleukin-10 (IL-10) may suppress not only inflammation but also induction of osteoclasts that play key roles in the bone destruction. If IL-10-producing osteoblast-like cells are induced from patient somatic cells and transplanted back into the destructive bone lesion, such therapy may promote bone remodeling by the cooperative effects of IL-10 and osteoblasts. We transduced mouse fibroblasts with genes for IL-10 and Runx2 that is a crucial transcription factor for osteoblast differentiation. The IL-10-producing induced osteoblast-like cells (IL-10-iOBs) strongly expressed osteoblast-specific genes and massively produced bone matrix that were mineralized by calcium phosphate in vitro and in vivo. Culture supernatant of IL-10-iOBs significantly suppressed induction of osteoclast from RANKL-stimulated Raw264.7 cells as well as LPS-induced production of inflammatory cytokine by macrophages. The IL-10-iOBs may be applicable to novel cell-based therapy against bone destruction associated with RA.

Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis.

Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. The role of MDSCs in autoimmune diseases remains controversial, and little is known about the function of MDSCs in autoimmune arthritis. In this study, we clarify that MDSCs play crucial roles in the regulation of proinflammatory immune response in a collagen-induced arthritis (CIA) mouse model. MDSCs accumulated in the spleens of mice with CIA when arthritis severity peaked. These MDSCs inhibited the proliferation of CD4(+) T cells and their differentiation into Th17 cells in vitro. Moreover, MDSCs inhibited the production of IFN-γ, IL-2, TNF-α, and IL-6 by CD4(+) T cells in vitro, whereas they promoted the production of IL-10. Adoptive transfer of MDSCs reduced the severity of CIA in vivo, which was accompanied by a decrease in the number of CD4(+) T cells and Th17 cells in the draining lymph nodes. However, depletion of MDSCs abrogated the spontaneous improvement of CIA. In conclusion, MDSCs in CIA suppress the progression of CIA by inhibiting the proinflammatory immune response of CD4(+) T cells. These observations suggest that MDSCs play crucial roles in the regulation of autoimmune arthritis, which could be exploited in new cell-based therapies for human rheumatoid arthritis.

A multicenter, single-arm, open-label interventional study of adherence to brexpiprazole during switching from previous antipsychotic drugs in patients with schizophrenia or schizoaffective disorder.

The rate of medication persistence was examined in patients with schizophrenia or schizoaffective disorder during switching from previously administered antipsychotics to brexpiprazole, a new dopamine D2 receptor partial agonist. A multicenter, single-arm, open-label 24-week interventional study was conducted, consisting of two 12-week consecutive periods: an initial switch (by plateau cross-titration) with the subsequent period, followed by a second maintenance period. Prior antipsychotics were olanzapine or risperidone/paliperidone. The primary and secondary outcome measures were medication persistence rates after the first 12 weeks and changes from baseline in the Specific Levels of Functioning Scale (SLOF), Subjective Well-being under Neuroleptic drug treatment Short form (SWNS), and Positive and Negative Syndrome Scale (PANSS) scores, respectively. In total, 79 patients were administered brexpiprazole and the medication persistence rate at 12 weeks was 78.5%, which was significantly higher than the predefined threshold of 65%. Regarding the prior medication, the persistence rate at 12 weeks was 84.6% for olanzapine and 72.5% for risperidone/paliperidone. Significant improvements from baseline were observed in the SLOF, SWNS, and PANSS scores. There were no adverse events of concern. Thus, brexpiprazole appeared to be a suitable antipsychotic on switching from olanzapine, risperidone, or paliperidone.

The rapid efficacy of abatacept in a patient with rheumatoid vasculitis.

We report a case of rheumatoid vasculitis (RV) that responded well to abatacept, a cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-immunoglobulin fusion protein. A 38-year-old woman developed RV despite treatment with methotrexate and tumor necrosis factor (TNF) inhibitors. The effects of steroid therapy, immunoabsorption plasmapheresis, and interleukin-6 inhibitor were insufficient, however, administration of abatacept rapidly improved her clinical symptoms with almost normalization of the immunological findings. This is the first published case report of the successful treatment of RV with abatacept.

Protocol for stratification of triple-negative breast cancer patients using in silico signaling dynamics.

Personalized kinetic models can predict potential biomarkers and drug targets. Here, we provide a step-by-step approach for building an executable mathematical model from text and integrating transcriptomic datasets. We additionally describe the steps to personalize the mechanistic model and to stratify patients with triple-negative breast cancer (TNBC) based on in silico signaling dynamics. This protocol can also be applied to any signaling pathway for patient-specific modeling. For complete details on the use and execution of this protocol, please refer to Imoto et al. (2022).

Therapeutic effects of vitamin A on experimental cholestatic rats with hepatic fibrosis.

PURPOSE: The aim of this study is to investigate the role of hepatic stellate cells (HSCs) and the effect of vitamin A administration on liver damage induced by bile duct ligation (BDL) and administration of CCl(4). METHODS: Two types of animal model were used; one was BDL as a model of biliary atresia, the other was CCl(4)-induced hepatic fibrosis. Pathological changes of the liver with or without administration of vitamin A were compared by light and electron microscopy with focusing on HSCs in each experimental group. Immunohistochemical examination was performed with anti-keratinocyte growth factor (KGF), anti-alpha-smooth muscle actin (α-SMA), and anti-glial fibrillary acidic protein (GFAP) antibodies, as markers of fibrosis. RESULTS: On light microscopic findings, periportal inflammation with bile ductular proliferation was obvious in BDL group and pericentral necrosis with fatty degeneration was observed in CCl(4) group, both of which were ameliorated by subcutaneous injection of vitamin A. Electron microscopy showed lipid droplets were almost depleted in the HSCs treated with BDL or CCl(4), which improved with vitamin A administration. Immunohistochemistry demonstrated that enhanced expression of all three fibrotic markers in the BDL group was diminished by vitamin A administration. CONCLUSIONS: Although most of our data are qualitative observation, vitamin A may ameliorate hepatic fibrosis in the BDL model by restoring vitamin A in the HSCs.

Clonal Cytopenia of Undetermined Significance in a Patient with Congenital Wilms' Tumor 1 and Acquired DNMT3A Gene Mutations.

Congenital mutations of the Wilms' tumor 1 (WT1) gene can lead to various abnormalities, including renal/gonadal developmental disorders and cardiac malformations. Although there have been many reports of somatic WT1 mutations in patients with acute myeloid leukemia and myelodysplastic syndrome, congenital WT1 mutations have not been reported in hematological disorders. We herein report a patient with early-onset clonal cytopenia of undetermined significance that was associated with a congenital mutation of WT1 and an acquired mutation of DNMT3A [encoding DNA (cytosine-5)-methyltransferase 3A].

A Rare Case of Chronic Subdural Hematoma Coexisting With Metastatic Tumor.

BACKGROUND: Incidence of chronic subdural hematoma (CSH) associated with metastases of extraneural malignancies is rare. We report a rare case of CSH wherein most of the CSH cavity was occupied with metastatic cancer cells; in addition, we review the literature. CASE DESCRIPTION: A 68-year-old man with a history of gastric cancer presented to our hospital with dysarthria and shoulder paralysis; CSH was diagnosed from preoperative imaging findings. When the hematoma was removed via a small craniotomy, besides the hematoma, we observed an abnormal mass of tissue in the capsule. Pathologically, the mass was consistent with the findings of metastatic gastric cancer. Although the symptoms immediately disappeared postoperatively, a symptomatic acute subdural hematoma with midline shift was observed on postoperative day 27. Emergency craniotomy and hematoma and tumor removal were performed. Pathologic examination showed hemorrhagic necrosis in the tumor, which had not been initially observed. The postoperative course progressed without hematoma recurrence. CONCLUSIONS: To the best of our knowledge, this is the first report of a CSH accompanied by tumor metastasis in most of the CSH cavity. Although rare, if a patient with cancer has CSH, the CSH should be treated considering the possibility of metastasis.

Morphological characteristics of infected subdural hematoma: Comparison with images of chronic subdural hematoma.

OBJECTIVES: Infected subdural hematoma (ISH) is a rare type of subdural empyema, with fewer than 50 cases reported to date. Its radiological features have not been adequately described, making diagnosis challenging. At our institution, two adults presented with ISH, which exhibited a characteristic shape on preoperative imaging. PATIENTS AND METHODS: This study examined ISH cases and chronic subdural hematoma (CSH) cases that underwent surgery at the Ishikawa Prefectural Central Hospital between January 2016 and March 2018. To distinguish ISH from CSH, we focused on three specific radiological features: the biconvex shape of the hematoma, presence of a high-density region at the lower end of the hematoma on plain computed tomography (CT), and presence of a hyper-intense signal within the hematoma on diffusion weighted imaging (DWI). RESULTS: We analyzed 30 ISH (current and previously reported) and 102 CSH cases in our study. We found no statistically significant associations between the hematoma type (ISH or CSH) and the presence of a high-density region at the lower end of the hematoma on plain CT (p = 0.13) or the presence of hyperintensity in the hematoma on DWI (p = 1.00). Conversely, a statistically significant association was found between the hematoma type and the biconvex shape of the hematoma (p < 0.01). CONCLUSION: These results suggest that the shape of the hematoma on imaging provides valuable information that can be used to differentiate ISH from CSH and optimize therapeutic approaches.

Upregulation of sphingosine-1-phosphate receptor 3 on fibroblast-like synoviocytes is associated with the development of collagen-induced arthritis via increased interleukin-6 production.

BACKGROUND: Sphingosine-1-phosphate receptor 3 (S1P3) is one of five receptors for sphingosine-1-phosphate (S1P). S1P/S1P3 signaling is involved in numerous physiological and pathological processes including bone metabolism, sepsis, cancer, and immunity. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) are activated by several factors and promote abundant proinflammatory cytokine production and bone destruction. The aim of this study was to investigate whether S1P3 is associated with the development of autoimmune arthritis and the pathogenic function of FLSs. METHODS: Wild-type (WT) and S1P3 knockout (S1P3-KO) collagen-induced arthritis (CIA) mice were evaluated with respect to clinical and histological disease severity, along with the levels of anti-collagen antibodies and expression of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6). S1P3 expression in the synovium was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. FLSs isolated from CIA mice were activated with TNFα and S1P3 expression was analyzed by real-time RT-PCR. The role of S1P/S1P3 signaling in activated and non-activated FLSs was investigated by measuring cell proliferation and cyto/chemokine production by real-time RT-PCR and/or enzyme-linked immunosorbent assay. RESULTS: Clinical and histological scores, and synovial IL-6 expression were significantly lower in S1P3-KO mice with CIA than in WT mice. Arthritic synovia had higher S1P3 expression than intact synovia and FLSs in arthritic joints expressed S1P3 in vivo. Primary cultured FLSs produced IL-6 in a time-dependent manner in response to S1P stimulation and exhibited higher levels of S1P3 expression after activation with TNFα. S1P3-induced production of IL-6 and MMP-3 was increased in FLSs pre-activated with TNFα. CONCLUSION: In this study, we demonstrated that S1P3 expression is associated with the development of autoimmune arthritis via inflammation-induced increases in S1P/S1P3 signaling that increase production of IL-6 in FLSs. Inhibition of S1P/S1P3 signaling could open the door to the development of new therapies for RA.

Convenient chirality transfer from organics to titania: construction and optical properties.

Polyethyleneimine (PEI) complexed with chiral d- (or l-) tartaric acid (tart) in water can self-organize into chiral and crystalline PEI/tart assemblies. It has been previously confirmed that the complexes of PEI/tart could work as catalytic/chiral templates to induce the deposition of SiO2 nanofibres with optical activity but without outwards shape chirality such as helices. In this work, we found that the templating functions of PEI/tart were still effective to prompt the deposition of TiO2 to form chiral PEI/tart@TiO2 hybrid nanofibres under aqueous and room temperature conditions within two hours. Furthermore, the co-deposition of TiO2 and SiO2 was also fulfilled to yield chiral PEI/tart@TiO2/SiO2 nanofibres. These TiO2-containing hybrid nanofibres showed non-helical shapes on the length scale; however, chiroptical signals with mirror relation around the UV-Vis absorption band of TiO2 remarkably appeared on their circular dichroism (CD) spectra. By means of the protocols of XRD, TEM, SEM, UV-Vis, CD and XPS, structural features and thermoproperties of the chiral TiO2 and SiO2/TiO2 were investigated.

Enlargement of Langerhans cell histiocytosis of the hypothalamus with progression into the basal ganglia and white matter.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease that may affect the central nervous system; it is caused by dendritic cell proliferation, and typically occurs in children. LCH frequently appears in the pituitary stalk and rarely results in multiple enhanced lesions in the brain parenchyma. CASE DESCRIPTION: We present a case of a 40-year-old woman who deveolped panhypopituitarism and central diabetes insipidus in the postpartum period requiring hormone replacement therapy. At first, magnetic resonance imaging only revealed thickening of the pituitary stalk; while 6 months later, a single enhanced mass lesion was detected in the hypothalamus. Another 5 months later, the lesion had enlarged with appearance of multiple, enhanced satellite lesions in the basal ganglia and white matter. The patient underwent successful craniotomy to obtain a biopsy sample; LCH of the hypothalamus was definitively diagnosis by histopathological examination. Steroids were administrated and resulted in significant reduction of all lesions. CONCLUSIONS: Definitive histopathological diagnosis and subsequent appropriate therapy, such as steroid administration, are required when LCH lesions in the hypothalamus become progressively enlarged and new lesions appear in the brain parenchyma.

Comparative effectiveness of switching paroxetine formulation for treatment of major depressive disorder: an open-label multicenter study.

AIM: To assess the effectiveness and safety of switching the antidepressant formulation from immediate-release (IR) to controlled-release (CR) paroxetine in patients with major depressive disorder (MDD). PATIENTS AND METHODS: A total of 113 outpatients with MDD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, and treated with a stable dose of IR paroxetine for at least 6 months were enrolled. Patients were then switched to CR paroxetine for 8 weeks. Effectiveness was evaluated by scores on the Himorogi Self-Rating Depression/Anxiety Scales (HSDS/HSAS) and the Clinical Global Impression - Severity (CGI-S). Safety was evaluated based on the reported adverse drug reactions (ADRs). Medication satisfaction and preference were assessed based on questionnaire responses using Likert-type scales. RESULTS: The overall patient HSDS/HSAS scores significantly improved after switching from IR to CR paroxetine (P<0.001). Furthermore, CR paroxetine was superior to IR paroxetine (P<0.001) according to the results of the CGI-S evaluation. ADRs were experienced by 14 (12.4%) patients, including dry mouth, nausea/vomiting, somnolence/drowsiness, and wakefulness/arousal during sleep. Satisfaction and preference for paroxetine improved after switching to the CR formulation (P<0.001; chi-square test). CONCLUSION: These results suggest that switching the treatment from IR to CR paroxetine could improve depressive symptoms and decrease ADRs. However, these results may have been caused by the psychological effect of drug switching. Hence, future studies with blinded evaluation methods are required to confirm and expand our findings.

Efficacy of abatacept in patients with rheumatoid arthritis, as assessed by magnetic resonance imaging of bilateral hands.

AIM: To examine the efficacy of abatacept in patients with rheumatoid arthritis (RA) using magnetic resonance imaging (MRI) of bilateral hands. METHOD: This prospective study included 35 RA patients. MRI of bilateral hands was performed at baseline and after 12 months of treatment with intravenous abatacept. MRI images were scored for synovitis, osteitis, erosion and joint space narrowing (JSN) according to the RA MRI Scoring System (RAMRIS). The primary endpoint was the change in RAMRIS score from baseline. Repair of erosion was defined as a negative change in the erosion score that was greater than the smallest detectable changes (SDCs). RESULTS: Thirty-one patients completed the study. Median synovitis and osteitis scores showed statistically significant reductions at Month 12 when compared to baseline (synovitis score, -5.5 [P < 0.0001]; osteitis score, -0.5 [P = 0.03]). However, median erosion and JSN scores did not significantly change. At Month 12, 83% of patients showed no progression of erosion scores and repair of erosion was observed in 11% of patients. All patients with repair of erosion achieved functional remission (Health Assessment Questionnaire-Disability Index ≤ 0.5). The Simplified Disease Activity Index response rate at Month 1 was identified as an independent factor predicting changes in the erosion scores at Month 12. CONCLUSION: Abatacept treatment reduced synovitis and osteitis scores and did not worsen erosion and JSN scores at Month 12. Over 10% of patients experienced repair of erosion.

Open versus arthroscopic surgery for internal derangement of the temporomandibular joint: a retrospective study comparing two centres' results using the Jaw Pain and Function Questionnaire.

OBJECTIVES: Surgical procedures currently used for treating of internal derangement of the temporomandibular joint vary widely. Although different studies present favourable results following open or arthroscopic TMJ surgery, the criteria for a successful treatment outcome are not always defined identically. In a retrospective study, two groups of patients who underwent either open or arthroscopic surgery for internal derangement (stages III-V according to Wilkes' classification) were investigated using the so-called JPF-Questionnaire. PATIENTS AND METHODS: The Kyoto collective (group 1) consisted of 28 patients, 2 men and 26 women, who underwent arthroscopic surgery. At the time of surgery, age ranged from 13 to 77 years (mean 32.8 y). The postoperative follow-up period ranged from 4 years and 4 months to 5 years and 9 months. Twelve of the 28 patients were classified as stage III, 10 as stage IV and 6 were classified as stage V (according to Wilkes) at the time of surgery. The Vienna collective (group 2) also consisted of 28 patients, 2 men and 26 women, who underwent open meniscoplasty or discectomy. At the time of surgery age ranged from 17 to 55 years (mean 31.6 years). The postoperative follow-up ranged from 5 to 6 years and 9 months. Fourteen of the 28 patients were classified as stage III, 11 as stage IV and 3 were classified as stage V (according to Wilkes) at the time of surgery. The results of the JPF-Questionnaire of the two groups were compared by Wilcoxon 2-sample tests. The Japanese version was applied, while in Austria the German version of this questionnaire was applied. RESULTS: At a level of significance alpha=0.05 no significant difference was found when comparing the subgroups (Wilkes stages III, IV and V) or both groups of patients 5 years after temporomandibular joint surgery. CONCLUSION: There cannot be any clear indication for only one of the treatment modalities as similar results were noted following open or arthroscopic temporomandibular joint surgery. Nevertheless, arthroscopic surgery is a minimally invasive procedure resulting in a shorter or no time of hospitalization when compared with open surgery and therefore is preferred by many surgeons nowadays.

Cross-cultural adaptation of the JPF-Questionnaire for German-speaking patients with functional temporomandibular joint disorders.

OBJECTIVES: Clinical research related to the management of the syndrome of temporomandibular joint pain and dysfunction would be facilitated enormously between researchers in different locations around the world if a small number of patient-oriented questionnaires were to achieve wide acceptance. It would make comparison of therapeutic results possible. For this reason, a cross-cultural version of the Jaw Pain and Function (JPF)-Questionnaire was developed and validated for use in German-speaking patients with functional temporomandibular disorders. MATERIAL AND METHODS: The scale was translated from the English into the German language and translated back into English again, pretested and reviewed by a committee. The German version of the JPF-Questionnaire was tested on 137 patients with temporomandibular disorders. Reliability and concurrent construct validity were assessed using Pearson's correlation coefficients. RESULTS: The concurrent validity was assessed by evaluating the relation of the questionnaire's summary score (the internal criterion) to data on maximum interincisal distance (the external criterion). Spearman's and correlation coefficients were statistically significant for the comparison of the summary score with maximal mouth opening (r=-0.213; p=0.036). Test-retest reliability for the JPF-Questionnaire was also assessed by Spearman's correlation coefficients: at first admission at the clinic (time a, mean=20.23+/-16.42, median=16), then at the time of administration 1 day later at home (time b, mean=17.98+/-16.29, median=13), and 7 days later at home (time c, mean=17.90+/-15.77, median=13). They were r=0.91 (p=0.0001) for the initial administration with the repetition 1 day later, r=0.90 (p=0.0001) for the initial administration with the repetition 1 week later, and r=0.93 (p=0.0001) for the correlation between the two repetitions. Test - retest reliability measured by mean-against-difference graphs was not satisfactory for time (a) versus time (b) and time (a) versus time (c) but there was a good test-retest reliability for time (b) versus time (c). CONCLUSION: The use of this instrument can be recommended in future clinical trials, as the German version of the JPF-Questionnaire seems to be valid and--under the same test-retest conditions--reliable for the assessment of temporomandibular joint disorders.

Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors.

Two controversial issues regarding p53 are whether it is involved in apoptosis induction of tumor cells by a histone deacetylase (HDAC) inhibitor and, given that p53 is indeed involved, which genes of acetylated p53 targets are responsible for giving rise to apoptotic death. We, in the present study, first confirmed that some substantial extent of apoptotic cell death was seen when p53-deficient cells (KATO-III) were transfected with wild-type p53 and treated with sodium butyrate (SB) or trichostatin A. By Western blotting, using specific antibodies, we then demonstrated that residues 320, 373, and 382 lysines of p53 were acetylated in KATO-III cells transfected with wild-type p53 (KATO-III/p53) treated with a HDAC inhibitor. However, as revealed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining, only those KATO-III cells transfected with K320R p53 or K373R p53 became insensitive to the HDAC inhibitor, suggesting that these two residues of p53 may be essential for HDAC inhibitor-induced apoptosis, whereas others such as K382R p53 may not. Furthermore, reverse transcription-PCR demonstrated that among various p53-related proapoptotic genes, expression of PIG3 and NOXA were clearly enhanced by SB treatment in KATO-III/p53 cells but not in KATO-III/K320R or KATO-III/K373R cells. Finally, we revealed that apoptosis could be evoked by SB even in cells where p53 mutations occur at residues other than 320 lysine or 373 lysine (TMK-1 and HSC-39 cells) and that this apoptosis was significantly, although not totally, suppressed by the anti-p53 antisense. It was, therefore, concluded that acetylation of the p53 molecule at residues 320 and 373, giving rise to up-regulation of PIG3 and NOXA, is one of the mechanisms for induction of apoptosis by HDAC inhibitors in cancer cells.