An oral triple pill-based cocktail effectively controls acute myeloid leukemia with high translation.

Acute myeloid leukemia (AML) is a deadly hematological malignancy characterized by oncogenic translational addiction that results in over-proliferation and apoptosis evasion of leukemia cells. Various chemo- and targeted therapies aim to reverse this hallmark, but most show only modest efficacy. Here we report a single oral pill containing a low-dose triple small molecule-based cocktail, a highly active anti-cancer therapy (HAACT) with unique mechanisms that can effectively control AML. The cocktail comprises oncogenic translation inhibitor HHT, drug efflux pump P-gpi ENC and anti-apoptotic protein Bcl-2i VEN. Mechanistically, the cocktail can potently kill both leukemia stem cells (LSC) and bulk leukemic cells via co-targeting oncogenic translation, apoptosis machinery, and drug efflux pump, resulting in deep and durable remissions of AML in diverse model systems. We also identified EphB4/Bcl-xL as the cocktail response biomarkers. Collectively, our studies provide proof that a single pill containing a triple combination cocktail might be a promising avenue for AML therapy.

UBE2L3 Reduces TRIM21 Expression and IL-1ß Secretion in Epidermal Keratinocytes and Improves Psoriasis-Like Skin.

Proinflammatory cytokines, such as IL-1ß, are important mediators of psoriasis. UBE2L3, an E2 enzyme, is thought to be an indirect target of IL-1ß secretion by binding to ubiquitin ligases such as TRIM21. However, its role in psoriasis remains unknown. In this study, we found that UBE2L3 expression was decreased in psoriatic epidermis, whereas caspase 1 and IL-1ß signaling were strongly activated. When normal human epidermal keratinocytes were stimulated with nigericin, adenosine triphosphate, and poly(dA:dT), downregulation of UBE2L3 and increased secretion of IL-1ß were observed. Treatment with a caspase 1 inhibitor reversed the decrease in the level of UBE2L3. In addition, UBE2L3 overexpression reduced TRIM21, decreased signal transducer and activator of transcription 3 pathway activity, and reduced the level of the IL-1ß precursor (pro‒IL-1ß). Consistently, silencing UBE2L3 enhanced TRIM21 expression, signal transducer and activator of transcription 3 activation, and pro‒IL-1ß production. Finally, in an imiquimod-induced mouse model, UBE2L3 reduction and caspase 1 activation were localized in the epidermis, whereas overexpression of UBE2L3 ameliorated psoriasis-like lesions and reduced pro‒IL-1ß and mature IL-1ß levels in the epidermis. Thus, UBE2L3 may be a protective biomarker that regulates IL-1ß and inhibits TRIM21 in the epidermis of psoriasis.

Primary hepatopancreatobiliary lymphoma: Pathogenesis, diagnosis, and management.

Primary hepatopancreatobiliary lymphoma (PHPBL) is extremely rare, which is defined as a lympho-proliferative disease confined to the hepatobiliary system and pancreas without any involvement of lymph nodes, bone marrow, or other organs. The clinical and imaging manifestations of PHPBL are variable and non-special, which are akin to those of tumors of the hepatobiliary and pancreatic systems. The overall prognosis and management of PHPBL differ from those of other tumors in the hepatobiliary system and pancreas. Proper diagnosis and prompt treatment are essential for improving clinical outcomes. Due to its rarity, the optimal treatment has not been issued. However, combination chemotherapy is considered as a standard treatment for them. This review provides an overview of the pathogenesis, diagnosis, pathology, and management of PHPBL and offers clinicians the diagnosis and management schedule for PHPBL.

Aberrantly Activated APOBEC3B Is Associated With Mutant p53-Driven Refractory/Relapsed Diffuse Large B-Cell Lymphoma.

Tumor protein 53 (TP53) mutation predicts an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL), but the molecular basis for this association remains unclear. In several malignancies, the cytidine deaminase apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) has been reported to be associated with the TP53 G/C-to-A/T mutation. Here, we show that the frequency of this mutation was significantly higher in relapsed/refractory (R/R) than in non-R/R DLBCL, which was positively associated with the APOBEC3B expression level. APOBEC3B overexpression induced the TP53 G/C-to-A/T mutation in vitro, resulting in a phenotype similar to that of DLBCL specimens. Additionally, APOBEC3B-induced p53 mutants promoted the growth of DLBCL cells and enhanced drug resistance. These results suggest that APOBEC3B is a critical factor in mutant p53-driven R/R DLBCL and is therefore a potential therapeutic target.

Dual-dispersion-regime dual-comb mode-locked laser.

We report on the first, to the best of our knowledge, solid-state dual-comb mode-locked laser that simultaneously operates in different dispersion regimes. Due to the intrinsic polarization multiplexing in a birefringent Yb:Ca3NbGa3Si2O14 (Yb:CNGS) gain medium, the laser emits two cross-polarized pulse trains with a repetition rate offset of ∼ 4.8 kHz from a single cavity. We obtain dual pulse generation with a 20-fold difference in duration by setting the net cavity group delay dispersion to cross zero across the emission band of the employed gain medium. While the duration of the soliton-like pulses experiencing anomalous dispersion amounts to 117 fs, the second laser output, which is spectrally located in the normal dispersion region, is strongly chirped with a pulse duration of 2360 fs.

A Selective Small-Molecule c-Myc Degrader Potently Regresses Lethal c-Myc Overexpressing Tumors.

MYC oncogene is involved in the majority of human cancers and is often associated with poor outcomes, rendering it an extraordinarily desirable target, but therapeutic targeting of c-Myc protein has been a challenge for >30 years. Here, WBC100, a novel oral active molecule glue that selectively degrades c-Myc protein over other proteins and potently kills c-Myc overexpressing cancer cells is reported. WBC100 targets the nuclear localization signal 1 (NLS1)-Basic-nuclear localization signal 2 (NLS2) region of c-Myc and induces c-Myc protein degradation through ubiquitin E3 ligase CHIP mediated 26S proteasome pathway, leading to apoptosis of cancer cells. In vivo, WBC100 potently regresses multiple lethal c-Myc overexpressing tumors such as acute myeloid leukemia, pancreatic, and gastric cancers with good tolerability in multiple xenograft mouse models. Identification of the NLS1-Basic-NLS2 region as a druggable pocket for targeting the "undruggable" c-Myc protein and that single-agent WBC100 potently regresses c-Myc overexpressing tumors through selective c-Myc proteolysis opens new perspectives for pharmacologically intervening c-Myc in human cancers.

Treatment of Central Nervous System Relapse in Acute Promyelocytic Leukemia by Venetoclax: A Case Report.

Extramedullary relapse of acute promyelocytic leukemia is a rare phenomenon and is associated with a poor prognosis, with the central nervous system being the most common site of relapse. The current treatments are still limited. Venetoclax, a selective inhibitor of BCL2, is a small molecule that can cross the blood-brain barrier and shows a potential efficacy in the treatment of chronic lymphocytic leukemia with central nervous system involvement. Although venetoclax has also been used in the treatment of acute myeloid leukemia in recent years, there are no reports of its use in the treatment of central nervous system relapse in acute promyelocytic leukemia. Here, we report a case of central nervous system relapse in acute promyelocytic leukemia that achieved complete remission after oral treatment with venetoclax. The presence of venetoclax in the patient's CSF was confirmed by testing CSF and plasma by mass spectrometry. The concentration of venetoclax in CSF was approximately 1/300 of that in plasma trough concentration. The treatment experience in this case demonstrates the potential ability of venetoclax to treat of central nervous system relapse/involvement in acute promyelocytic leukemia, thus providing a new treatment option for this kind of patient.

Myeloid sarcoma of the pancreas: A case report and literature review.

INTRODUCTION: Myeloid sarcoma (MS) is an extramedullary mass, consisting of myeloid blasts with or without maturation, which efface the normal tissue architecture. It occurs mainly in lymph nodes, skin and soft tissue, testis, bone, peritoneum, and gastrointestinal tract, but rarely in the pancreas. Because their clinical courses, treatments, and prognoses are quite different, it is crucially important to distinguish between MS and pancreatic cancer. PATIENT CONCERNS: We herein report a rare case of acute myeloid leukemia (AML) which presented with a pancreatic mass that mimicked pancreatic cancer.Diagnosis: The diagnosis of MS was established based on immunohistochemical (IHC) analysis and bone marrow examination which revealed neoplastic cells with CD34+/CD117+. INTERVENTIONS: The patient was actively treated with chemotherapy. OUTCOMES: After 4 cycles of chemotherapy, the lesion in pancreas was significantly reduced, and the patient is still receiving further chemotherapy. CONCLUSION: When we encounter a patient suspected of pancreatic cancer with blood cell abnormalities and no significant increase in carbohydrate antigen 19-9 (CA19-9), we need to be aware of the possibility of pancreatic MS. Preoperative pathological biopsy and IHC are indispensable. Misdiagnosis is common if we rely solely on imaging.

Targeting miR-21 with NL101 blocks c-Myc/Mxd1 loop and inhibits the growth of B cell lymphoma.

Background: NL101 has shown activities against multiple myeloma and acute myeloid leukemia, but its anti-lymphoma activity remains unknown. The transcription factor c-Myc is frequently dysregulated in aggressive B cell lymphomas such as double-hit lymphoma, for which the standard of care is still lacking. A novel approach to target c-Myc needs to be explored. Although the role of oncogenic microRNA-21 (miR-21) was well established in an inducible mice model of B cell lymphoma, whether targeting miR-21 could inhibit the growth of B cell lymphoma and its underlying mechanisms is unclear. Methods: We used MTT assay and flow cytometry to determine the inhibitory effect of NL101 on the cell proliferation of B cell lymphoma in vitro. The lymphoma xenograft mice models were generated to evaluate the anti-lymphoma function in vivo. Western blot and qPCR were applied to measure the expression levels of protein and microRNA, respectively. To investigate the mechanisms of action in NL101, we used genechip to profile differentially-expressed genes upon NL101 induction. Luciferase reporter system and chromatin immunoprecipitation were used for the validation of target gene or miRNA. Results: Nl101 significantly inhibited B cell lymphoma proliferation through induction of cell cycle arrest and apoptosis. NL101 suppressed the growth of B cell lymphoma in vivo and prolonged the survival of lymphoma xenograft models. Gene expression profiling revealed that miR-21 was significantly decreased upon the induction of NL101 in B cell lymphoma. The miR-21 level was associated with the sensitivity of NL101. miR-21 inhibited Mxd1 expression via directly combining to Mxd1 3'-UTR; c-Myc activated miR-21 expression by directly binding to the miR-21 promoter. Conclusion: NL101 significantly inhibited the growth of B cell lymphoma in vitro and in vivo. The novel c-Myc/miR-21/Mxd1 positive-feedback loop is critical for the maintenance of B cell lymphoma survival. Targeting miR-21 to block c-Myc/miR-21/Mxd1 loop represents a novel potential strategy of c-Myc-directed therapy.

Identification of the novel Np17 oncogene in human leukemia.

We previously defined the HERV-K Np9 as a viral oncogene. Here we report the discovery of a novel oncogene, Np17, which is homologous to the viral Np9 gene and predominantly present in Hominoidea. Np17 is located on chromosome 8, consists of 7 exons, and encodes a 16.8kDa nuclear protein with149 amino-acid residue. Functionally, knockdown of Np17 induced growth inhibition of leukemia cells, whereas enforced expression of Np17 promoted growth of leukemia cells in vitro and in vivo. In human leukemia, Np17 was detected in 59.65% (34/57) of acute myeloid leukemia (AML) patients examined and associated with refractory/relapsed AML. Mechanistically, Np17 decreased p53 levels and its mechanism might be involved in recruiting nuclear MDM2 to p53 for ubiquitin-mediated degradation. These findings reveal that Np17 is a novel oncogene associated with refractory/relapsed leukemia.

Clearance of HBsAg in a patient with familial multiple myeloma after a bortezomib-based regimen combined with anti-HBV drug: A case report.

RATIONALE: Reactivation of hepatitis B virus (HBV) after treatment with bortezomib-based regimens in HBV-positive patients with multiple myeloma (MM) has been reported in the past few years. Nevertheless, there is evidence of inhibition of HBV replication by bortezomib in transgenic mice. However, there is still no clinical evidence that bortezomib inhibits HBV. PATIENT CONCERNS: A 55-year-old MM patient with a family history of MM, who was also a chronic HBV carrier, achieved HBV clearance after treatment with a bortezomib-based regimen in combination with anti-HBV drugs. DIAGNOSES: The diagnosis was MM with chronic carrier of HBV. INTERVENTIONS: He received bortezomib-based regimen for MM as well as entecavir as a prophylaxis to prevent HBV reactivation. OUTCOMES: This patient achieved HBsAg and HBV-DNA clearance after 2 months and the remission was maintained during the next 2 years. He also achieved complete remission of MM and underwent consolidation therapy with autologous hematopoietic stem cell transplantation. LESSONS: This is the first case of MM with HBV clearance after receiving a bortezomib-based regimen combined with anti-HBV drug. Research on related mechanisms might provide new suggestions and hope for better management of HBV positive patients with MM and for the treatment of HBV patients.

The N gene of SARS-CoV-2 was the main positive component in repositive samples from a cohort of COVID-19 patients in Wuhan, China.

BACKGROUND: Repositivity of SARS-CoV-2 nucleic acid in discharged COVID-19 patients was reported recently. However, the characteristics of repositive results are still not well understood, leading to a lack of effective monitoring strategies. METHODS: In the present study, a total of 59 COVID-19 patients were enrolled, and the characteristics of the repositive samples were analyzed. RESULTS: The repositive rate in this cohort was 15.79%. The N gene was the main target gene that was positive in the repositive results as well as in the last positive results of all patients. The median duration from diagnosis to the last positive test was 20 days (IQR, 16-31 days), and the longest duration was 40 days. Repositivity was only observed in IgM single- or both IgM- and IgG-positive patients, instead of IgG single-positive patients. CONCLUSIONS: There was a significant proportion of repositives in the recovered COVID-19 patients, and increasing the required number of negatives for consecutive nucleic acid tests may reduce the incidence of repositives. The recommended monitoring strategy for repositivity is monitoring the N gene in IgM-positive patients. This can ensure high sensitivity while reducing the time and cost of nucleic acid detection.

Aberrant activation of RPB1 is critical for cell overgrowth in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a group of highly aggressive malignancies with a 5-year overall survival of less than 40%. Cell overgrowth with defective apoptosis is a hallmark of AML, but little is known about how it occurs. Here, we show that aberrant activation of the largest subunit of RNA polymerase II (RPB1) encoded by POLR2A gene is critically involved in this hallmark. We retrospectively analyzed the expression profiles of POLR2A and RPB1 in a panel of AML cell lines, primary AML patients and peripheral blood samples. Meanwhile, correlation analysis was used to explore the correlation between the expression of RPB1 with tumor burden and overall survival time in untreated AML samples. RNA-Seq approach was performed to identify the differentially expressed genes between RPB1 silencing AML cells with control cells after knocking out RPB1. Furthermore, orthotopic AML models were established with RPB1 silencing and control cells to investigate the effects of RPB1 protein level on leukemia cell growth. In most AML patients, RPB1 was aberrantly activated and closely associated with poor prognosis, but not in normal hematopoietic cells. Global transcriptomic analysis revealed that POLR2A knockout strongly impaired growth of AML cells by selectively depleting a substantial set of AML-related oncogenic and anti-apoptosis genes such as MYC, RUNX2, MEIS1, CDC25A and BCL-2. Silencing RPB1 by genetic technology led to a potent regression of human refractory AML in mouse models. These findings reveal that dysregulated RPB1 is a central oncogenic hub that drives overgrowth by hijacking an array of oncogenic and anti-apoptosis factors. Targeting RPB1 is a potential therapeutic for treating AML.

Acute lymphoblastic leukemia with pancreas involvement in an adult patient mimicking pancreatic tumor: A case report.

RATIONALE: Acute lymphoblastic leukemia (ALL) is a malignant disease originating from abnormal proliferation of B or T lymphocytes in bone marrow (BM). Invasion of the pancreas is extremely rare in adults. PATIENT CONCERNS: In this article, we report a case presenting that ALL invades the pancreas, as well as liver, kidney, and duodenum detected by magnetic resonance image. The patient was misdiagnosed as pancreatic tumor at initial since hemogram was unremarkable. DIAGNOSES: The diagnosis of ALL was established based on the endoscopic ultrasonography-guided fine-needle aspiration and bone marrow examination, showing BCR/ABL gene positive. INTERVENTIONS: The patient was actively treated with chemotherapy. Hematological remission was obtained and the lesions in the pancreas disappeared. OUTCOMES: The patient finally died of complication from fungal pneumonia and central nervous system involvement 12 months after diagnosis. LESSONS: Under the context of infection, persistent or intermittent fever and complete blood count are not significant prognoses of pancreatic involvement for adult with ALL. We hope that this case will help hepatobiliary and pancreatic surgeon to be aware of this kind of disease as pancreatic carcinoma and pancreas involvement by ALL have totally different treatment strategy.

Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia.

As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML.

Graphene and SESAM mode-locked Yb:CNGS lasers with self-frequency doubling properties.

We report on mode-locking of an Yb:Ca3NbGa3Si2O14 laser, which is pumped by a fiber-coupled single-mode laser diode. The shortest pulse duration obtained with a semiconductor saturable absorber mirror is 52 fs, with 75 mW of average output power. Sub-60 fs operation tunable between 1055 and 1074 nm is achieved by employing semiconductor absorbers with different characteristics. We also demonstrate passive mode-locking results with transmissive graphene saturable absorber, reaching an 85 fs pulse duration with 23 mW output power. Moreover, we present the non-phase-matched self-frequency doubling properties of this non-centrosymmetric crystal in the femtosecond regime.

Efficient laser operations of unprocessed thin plate of Nd:YPO4 crystal.

The laser properties of Nd:YPO4 crystal were demonstrated for the first time. For a 1.2 at.% doped Nd:YPO4 crystal, the absorption cross-section at 803 nm, stimulated emission cross-section at 1063 nm, and fluorescence lifetime was measured to be 8.1 × 10-20 cm2, 1.6 × 10-19 cm2, 156 µs, respectively. With an as-grown 0.6 mm thin slice which was unpolished and uncoated, efficient diode-pumped continue-wave (CW) laser operations were realized at 1.06 and 1.3 µm wavebands. The 1063 nm output power reached 2.16 W when the absorbed pump power was 4.07 W, corresponding to an optical-to-optical efficiency of 53%, and a slope efficiency of 56.4%. The 1.3 µm laser output exhibited the simultaneous operations of dual-wavelengths, i.e. 1338 and 1347 nm. The maximum output power was 800 mW at an absorbed pump power of 3.08 W, giving an optical-to-optical efficiency of 26% and a slope efficiency of 28.2%.

Passive Q switching of Yb:CNGS lasers by Cr4+:YAG and V3+:YAG saturable absorbers.

Trigonal langasite-type ordered silicate crystal Yb:Ca3NbGa3Si2O14 (Yb:CNGS) is a promising material for efficient ∼1 µm lasers. We report on the first passively Q-switched Yb:CNGS laser using Cr4+:YAG and V3+:YAG saturable absorbers (SAs) with a 976 nm volume-Bragg-grating-stabilized diode as a pump source. The laser crystal was a c cut 3 at.% Yb:CNGS grown by the Czochralski method. It was placed in a compact microchip-type laser cavity. With a Cr4+:YAG SA, very stable 62.2 µJ/4.4 ns pulses were achieved at a repetition rate of 22.5 kHz. The average output power was 1.40 W at 1015.3 nm, corresponding to a Q switching conversion efficiency of 90%. With the V3+:YAG SA, the pulse characteristics were 13.3 µJ/11.1 ns at a higher repetition rate of 68.4 kHz. The performance of the Yb:CNGS/Cr4+:YAG was numerically modeled showing a good agreement with the experiment.