Myeloid/natural killer (NK) cell precursor acute leukemia as a distinct leukemia type.

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.

Targeting Poly(ADP)ribose polymerase in BCR/ABL1-positive cells.

BCR/ABL1 causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In addition to the deregulatory effects of its kinase activity on cell proliferation, BCR/ABL1 induces genomic instability by downregulating BRCA1. PARP inhibitors (PARPi) effectively induce cell death in BRCA-defective cells. Therefore, PARPi are expected to inhibit growth of CML and Ph1-ALL cells showing downregulated expression of BRCA1. Here, we show that PARPi effectively induced cell death in BCR/ABL1 positive cells and suppressed colony forming activity. Prevention of BCR/ABL1-mediated leukemogenesis by PARP inhibition was tested in two in vivo models: wild-type mice that had undergone hematopoietic cell transplantation with BCR/ABL1-transduced cells, and a genetic model constructed by crossing Parp1 knockout mice with BCR/ABL1 transgenic mice. The results showed that a PARPi, olaparib, attenuates BCR/ABL1-mediated leukemogenesis. One possible mechanism underlying PARPi-dependent inhibition of leukemogenesis is increased interferon signaling via activation of the cGAS/STING pathway. This is compatible with the use of interferon as a first-line therapy for CML. Because tyrosine kinase inhibitor (TKI) monotherapy does not completely eradicate leukemic cells in all patients, combined use of PARPi and a TKI is an attractive option that may eradicate CML stem cells.

Internal Wireless Electrical Stimulation from Piezoelectric Barium Titanate Nanoparticles as a New Strategy for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive BC subtype with a higher metastatic rate and a worse 5-year survival ratio than the other BC. It is an urgent need to develop a noninvasive treatment with high efficiency to resist TNBC cell proliferation and invasion. Internal wireless electric stimulation (ES) based on piezoelectric materials is an emerging noninvasive strategy, with adjustable ES intensity and excellent biosafety. In this study, three different barium titanate nanoparticles (BTNPs) with different crystal phases and piezoelectric properties were studied. Varying intensities of internal ES were generated from the three BTNPs (i.e., BTO, U-BTO, P-BTO). In vitro tests revealed that the internal ES from BTNPs was efficient at reducing the proliferative potential of cancer cells, particularly BC cells. In vitro experiments on MDA-MB-231, a typical TNBC cell line, further revealed that the internal wireless ES from BTNPs significantly inhibited cell growth and migration up to about 82% and 60%, respectively. In vivo evaluation of MDA-MB-231 tumor-bearing mice indicated that internal ES not only resisted almost 70% tumor growth but also significantly inhibited lung metastasis. More importantly, in vitro and in vivo studies demonstrated a favorable correlation between the anticancer impact and the intensities of ES. The underlying mechanism of MDA-MB-231 cell proliferation and metastasis inhibition caused by internal ES was also investigated. In summary, our results revealed the effect and mechanism of internal ES from piezoelectric nanoparticles on TNBC cell proliferation and migration regulation and proposed a promising noninvasive therapeutic strategy for TNBC with minimal side effects while exhibiting good therapeutic efficiency.

Evaluation of the context of downstream N- and free N-glycomic alterations induced by swainsonine in HepG2 cells.

Swainsonine (SWA), a potent inhibitor of class II α-mannosidases, is present in a number of plant species worldwide and causes severe toxicosis in livestock grazing these plants. The mechanisms underlying SWA-induced animal poisoning are not fully understood. In this study, we analyzed the alterations that occur in N- and free N-glycomic upon addition of SWA to HepG2 cells to understand better SWA-induced glycomic alterations. After SWA addition, we observed the appearance of SWA-specific glycomic alterations, such as unique fucosylated hybrid-type and fucosylated M5 (M5F) N-glycans, and a remarkable increase in all classes of Gn1 FNGs. Further analysis of the context of these glycomic alterations showed that (fucosylated) hybrid type N-glycans were not the precursors of these Gn1 FNGs and vice versa. Time course analysis revealed the dynamic nature of glycomic alterations upon exposure of SWA and suggested that accumulation of free N-glycans occurred earlier than that of hybrid-type N-glycans. Hybrid-type N-glycans, of which most were uniquely core fucosylated, tended to increase slowly over time, as was observed for M5F N-glycans. Inhibition of swainsonine-induced unique fucosylation of hybrid N-glycans and M5 by coaddition of 2-fluorofucose caused significant increases in paucimannose- and fucosylated paucimannose-type N-glycans, as well as paucimannose-type free N-glycans. The results not only revealed the gross glycomic alterations in HepG2 cells induced by swainsonine, but also provide information on the global interrelationships between glycomic alterations.

Modulating p-Orbital of Bismuth Nanosheet by Nickel Doping for Electrocatalytic Carbon Dioxide Reduction Reaction.

Electrochemical reduction of CO2 (CO2 RR) to value-added chemicals is an effective way to harvest renewable energy and utilize carbon dioxide. However, the electrocatalysts for CO2 RR suffer from insufficient activity and selectivity due to the limitation of CO2 activation. In this work, a Ni-doped Bi nanosheet (Ni@Bi-NS) electrocatalyst is synthesized for the electrochemical reduction of CO2 to HCOOH. Physicochemical characterization methods are extensively used to investigate the composition and structure of the materials. Electrochemical results reveal that for the production of HCOOH, the obtained Ni@Bi-NS exhibits an equivalent current density of 51.12 mA cm-2 at -1.10 V, which is much higher than the pure Bi-NS (18.00 mA cm-2 at -1.10 V). A high Faradaic efficiency over 92.0 % for HCOOH is achieved in a wide potential range from -0.80 to -1.10 V, and particularly, the highest efficiency of 98.4 % is achieved at -0.90 V. Both experimental and theoretical results reveal that the superior activity and selectivity are attributed to the doping effect of Ni on the Bi nanosheet. The density functional theory calculation reveals that upon doping, the charge is transferred from Ni to the adjacent Bi atoms, which shifts the p-orbital electronic density states towards the Fermi level. The resultant strong orbital hybridization between Bi and the π* orbitals of CO2 facilitates the formation of *OCHO intermediates and favors its activation. This work provides an effective strategy to develop active and selective electrocatalysts for CO2 RR by modulating the electronic density state.

Wireless electrical stimulation at the nanoscale interface induces tumor vascular normalization.

Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve tumor vascular normalization. Polarized barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular calcium ion gradient by wireless electrical stimulation. In vivo tumor-bearing mouse model indicated that wireless electrical stimulation normalized tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant tumors.

Decrease of ABCB1 protein expression and increase of G1 phase arrest induced by oleanolic acid in human multidrug-resistant cancer cells.

Oleanolic acid (OA) is a natural compound that can be found in a number of edible and medicinal plants and confers diverse biological actions. However, the direct target of OA in human tumor cells remains poorly understood, preventing its application in clinical and health settings. A previous study revealed that overexpression of caveolin-1 in human leukemia HL-60 cells can increase its sensitivity to OA. The present study aimed to investigate the effects of OA on the doxorubicin-resistant human breast cancer MCF-7 cell line (MCF-7/DOX), harringtonine-resistant human leukemia HL-60 cells (HL-60/HAR) and their corresponding parental cell lines. Western blotting was performed to measure protein expression levels, whilst Cell Counting Kit-8 (CCK-8) assays, cell cycle analysis (by flow cytometry) and apoptosis assays (with Annexin V/PI staining) were used to assess drug sensitivity. CCK-8 assay results suggested that MCF-7/DOX cells, which overexpress the caveolin-1 protein, have similar OA susceptibility to their parent line. In addition, sensitivity of MCF-7/DOX cells to OA was not augmented by knocking down caveolin-1 using RNA interference. HL-60/HAR cells exhibited a four-fold increased sensitivity to OA compared with that in their parental HL-60 cells according to CCK-8 assay. Both of the resistant cell lines exhibited higher numbers of cells at G1 phase arrest compared with those in their parent lines, as measured via flow cytometry. Treatment of both MCF-7 cell lines with 100 µM OA for 48 h induced apoptosis, with increased effects observed in resistant cells. However, no PARP-1 or caspase-3 cleavage was observed, with some positive Annexin V staining found after HL-60/HAR cells were treated with OA, suggesting that cell death occurred via non-classical apoptosis or through other cell death pathways. It was found that OA was not a substrate of ATP-binding cassette subfamily B member 1 (ABCB1) in drug-resistant cells, as indicated by the accumulation of rhodamine 123 assessed using flow cytometry. However, protein expression of ABCB1 in both of the resistant cell lines was significantly decreased after treatment with OA in a concentration-dependent manner. Collectively, these results suggest that OA could reduce ABCB1 protein expression and induce G1 phase arrest in multidrug-resistant cancer cells. These findings highlight the potential of OA for cancer therapy.

MicroRNA302-367-PI3K-PTEN-AKT-mTORC1 pathway promotes the development of cardiac hypertrophy through controlling autophagy.

Cardiac hypertrophy at a decompensated state eventually leads to heart failure that mostly contributes to deaths globally. Dysregulated cardiac autophagy is a hallmark of a diseased heart, and a close contact between cardiac autophagy and cardiac hypertrophy is emerging. MicroRNAs (miRNAs) have been recently reported to be prominently implicated in cardiac hypertrophy through regulating cardiac autophagy. However, the role and function of miR302-367 clusters in cardiac autophagy and cardiac hypertrophy remain largely masked. Therefore, to investigate the performance of miR302-367 in cardiac hypertrophy, the specific in vitro hypertrophic model was established in H9c2 cells upon Ang II treatment. Consequently, we discovered a distinct inhibition on autophagy and a remarkable upregulation of miR302-367 expression in hypertrophic H9c2 cells. Besides, loss- and gain-of-function assays demonstrated miR302-367 inhibited autophagy and then aggravated cardiac hypertrophy. Mechanically, PTEN was predicted and confirmed as the shared target of miR302-367. Further, we recognized the apparent inactivation of PI3K/AKT/mTORC1 signaling in the face of miR302-367 suppression in Ang II-induced hypertrophic H9c2 cells. Moreover, co-treatment of PTEN inhibitor re-activated the PI3K/AKT/mTORC1 pathway, therefore counteracting the pro-autophagic and anti-hypertrophic effects of miR302-367 depletion on cardiomyocytes. These findings unveiled the pivotal role of the miR302-367 cluster in regulating cardiac autophagy and therefore modulating cardiac hypertrophy through PTEN/PI3K/AKT/mTORC1 signaling, indicating a promising therapeutic strategy for cardiac hypertrophy and even heart failure. Graphical abstract .

Adrenal Angiosarcoma: A Diagnostic Dilemma.

Primary angiosarcoma of the adrenal gland is both a rare and aggressive malignancy. Differentiating it from more common adrenal masses such as adrenal adenomas, adrenal cortical carcinomas, and metastatic carcinomas is one of several diagnostic challenges. Immunohistochemical analysis is imperative to arrive at the correct diagnosis. Treatment typically involves surgery and adjuvant chemotherapy, but prognosis remains poor.

Tumor necrosis factor-α-308 polymorphism is not associated with Kawasaki disease: A meta-analysis of case-control studies.

BACKGROUND: Genetic factors in the pathogenesis of Kawasaki disease (KD) have received a lot of attention during the past decade. Some studies have reported that tumor necrosis factor (TNF)-α-308 polymorphism has been associated with KD. However, there have been inconsonant results among different studies. To increase the power for clarifying the influence of TNF on KD, a meta-analysis of case-control studies were performed. METHODS: The following databases were searched to identify related studies: PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP databases according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Search terms included "Kawasaki disease" or "KD," "tumor necrosis factor-alpha" or "TNF-α," and "polymorphism" or "mutation." Two reviewers independently extracted data and assessed study quality using Newcastle-Ottawa Scale. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were used to assess the strength of the association. Accounting for heterogeneity, a fixed or random effects model was respectively adopted. Heterogeneity was checked using the Q test and the I statistic. A cumulative meta-analysis was conducted to estimate the tendency of pooled OR. Funnel plots and Egger tests were performed to test for possible publication bias and sensitivity analyses were done to ensure authenticity of the outcome. RESULTS: Eleven separate studies were suitable for the inclusion criterion. The selected studies contained 2582 participants, including 841 in KD group and 1741controls. The pooled odds ratio of G versus A with the random effect model was 1.09 (95% CI = 0.69-1.70, P = .72) and the genotype effects for GG versus GA+AA was 1.14 (95% CI = 0.68-1.90, P = .62) in the whole population separately. Unfortunately, no significant association was detected between the TNF-α-308 polymorphism and KD risk under allele and genotype model. CONCLUSION: No association between the TNF-α-308 polymorphism and KD was found in our meta-analysis and further studies with larger sample size and more ethnicities are expected to be conducted in the future to validate the results.

Foamy Histiocyte-like Esophageal Adenocarcinoma: Unusual Morphology and Diagnostic Pitfalls.

In the United States and other western countries, the vast majority of primary esophageal malignancies are adenocarcinomas arising in the lower esophagus within a background of Barrett's esophagus. The microscopic feature of esophageal adenocarcinoma varies, with the tubular or papillary adenocarcinoma of intestinal pattern being the most common, and other less common morphological patterns include adenosquamous, signet ring cell, mucinous, mucoepidermoid, and adenoid cystic carcinoma. This is a case report of esophageal adenocarcinoma with foamy histiocyte-like feature in a 71-year-old male with a history of smoking and Barrett's esophagus who presented with dysphagia and weight loss. The tumor cells showed an abundant foamy cytoplasm, low N/C ratio and irregular nuclear contour. They were arranged in single, trabecular and glandular patterns and deeply invaded adventitia. Lymphovascular invasion and perineural invasion were present. The foamy histiocyte like-tumor cells were negative for CD68, but strongly and diffusely positive for CK7. E-Cadherin was maintained in the tumor cells, and p53 immunostaining revealed a wild-type staining pattern. To the best of our knowledge, this is the first documented case of primary esophageal adenocarcinoma with foamy-histiocyte-like phenotype. The clinical course, diagnosis and prognosis of this entity are discussed.

Cytoreductive Surgery and Normothermic Intraperitoneal Chemotherapy for Signet Ring Cell Appendiceal Adenocarcinoma With Peritoneal Metastases in the Setting of Cirrhosis.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal surface malignancies (PSM). The objective of cytoreduction is to eradicate macroscopic disease, while HIPEC addresses residual microscopic disease. Currently, there are no protocols guiding treatment of cirrhotic patients with PSM. We report the case of a cirrhotic patient with signet ring cell (SRC) appendiceal adenocarcinoma who underwent normothermic, as opposed to hyperthermic intraperitoneal chemotherapy (IPC). A 50-year-old woman with compensated class A cirrhosis and chronic hepatitis B and C underwent a right hemicolectomy in 2007 and adjuvant chemotherapy in 2008 for appendiceal SRC adenocarcinoma. In 2011, she was found to have peritoneal disease after a laparotomy. She subsequently experienced intolerance to chemotherapy, with stable disease on serial restaging. In light of her cirrhosis, the decision was made to perform CRS and IPC without hyperthermia to treat her residual disease. In 2012, she underwent CRS (omentectomy, total abdominal hysterectomy, left salpingo-oophorectomy) and IPC with mitomycin C. Thirty-day postoperative morbidity included delayed abdominal closure (Clavien-Dindo Grade IIIb), prolonged ventilator support (IIIa), vasopressor requirements (II), and confusion (II). The patient's liver function remained stable. Eight months later, she had evidence of recurrence on computed tomography. Twenty-two months later, she developed an extrinsic compression secondary to evolving disease, requiring a palliative endoscopic stent. The patient expired from her disease 29 months after her CRS and IPC. The criteria guiding selection of suitable candidates for CRS continues to evolve. Concomitant compensated cirrhosis in patients with PSM should not constitute a reason independently to exclude CRS with intraperitoneal chemotherapy, given the oncologic benefits of the procedure.

Vasodilator-stimulated phosphoprotein promotes liver metastasis of gastrointestinal cancer by activating a ß1-integrin-FAK-YAP1/TAZ signaling pathway.

Extracellular matrix (ECM)-induced ß1-integrin-FAK signaling promotes cell attachment, survival, and migration of cancer cells in a distant organ so as to enable cancer metastasis. However, mechanisms governing activation of the ß1-integrin-FAK signaling remain incompletely understood. Here, we report that vasodilator-stimulated phosphoprotein (VASP), an actin binding protein, is required for ECM-mediated ß1-integrin-FAK-YAP1/TAZ signaling in gastrointestinal (GI) cancer cells and their liver metastasis. In patient-derived samples, VASP is upregulated in 53 of 63 colorectal cancers and 43 of 53 pancreatic ductal adenocarcinomas and high VASP levels correlate with liver metastasis and reduced patient survival. In a Matrigel-based 3-dimensional (3D) culture model, short hairpin RNA (shRNA)-mediated VASP knockdown in colorectal cancer cells (KM12L4, HCT116, and HT29) and pancreatic cancer cells (L3.6 and MIA PaCa-1) suppresses the growth of 3D cancer spheroids. Mechanistic studies reveal that VASP knockdown suppresses FAK phosphorylation and YAP1/TAZ protein levels, but not Akt or Erk-related pathways and that YAP1/TAZ proteins are enhanced by the ß1-integrin-FAK signaling. Additionally, VASP regulates the ß1-integrin-FAK-YAP1/TAZ signaling by at least two mechanisms: (1) promoting ECM-mediated ß1-integrin activation and (2) regulating YAP1/TAZ dephosphorylation at downstream of RhoA to enhance the stability of YAP1/TAZ proteins. In agreement with these, preclinical studies with two experimental liver metastasis mouse models demonstrate that VASP knockdown suppresses GI cancer liver metastasis, ß1-integrin activation, and YAP1/TAZ levels of metastatic cancer cells. Together, our data support VASP as a treatment target for liver metastasis of colorectal and pancreatic cancers.

Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation.

Autoimmune diseases in children are rare and can be difficult to diagnose.  Single causative genes have been identified for some pediatric autoimmune diseases. Such orphan diseases may not be diagnosed properly due to the variability of patients' phenotypes. Guidelines for the diagnostic process need to be developed. Fifteen patients with uncharacterized childhood autoimmune diseases with lymphoproliferation that had negative testing for autoimmune lymphoproliferative syndrome were subjected to whole-exome sequencing to identify genes associated with these conditions. Five causative genes, CTLA4, STAT3, TNFAIP3, IKZF1, and PSTPIP1, were identified. These genes should be considered as candidates for uncharacterized childhood autoimmune diseases with lymphoproliferation.

Mixed Adenocarcinoma and Squamous Cell Carcinoma of Duodenum: A Case Report and Review of the Literature.

Despite being the largest part of the human gastrointestinal (GI) tract, the small intestine accounts for only 1-1.4% of all GI malignancies. Adenocarcinoma is the most common primary small bowel malignancy, with the most common site being the duodenum. On the other hand, squamous cell carcinoma (SCC) of the duodenum is extremely uncommon. We report the first case of mixed adenocarcinoma and SCC occurring in the third part of duodenum (D3). Our patient, a 64-year-old female with history of GERD, hypertension, and IDDM presented with 4 weeks of nausea, vomiting, and abdominal pain. Tomographic imaging of her abdomen demonstrated a distended stomach and a proximal duodenum with narrow caliber changes at the level of D3. An EGD revealed a tight stricture at D3 that could not be traversed. Stricture biopsies revealed duodenal mucosa with two small foci of SCC (positive for p63 and CK5/6) and adenocarcinoma (positive for CK7 and Moc31). Peritoneal metastases were detected on exploratory laparotomy, making the tumor surgically incurable. As she progressively declined and with worsening liver enzymes and general debility, she was not a candidate for chemotherapy and was eventually discharged on home hospice. Small bowel SCC/adenocarcinoma is an exceedingly uncommon cancer, making further case reports such as ours important to understand the nature of this entity and establish management guidelines.

Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome.

BACKGROUND: Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well-characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS-dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS-like phenotype. OBJECTIVE: The aim of the present study was to elucidate the genetic cause of the ALPS-like phenotype. METHODS: Candidate genes associated with the ALPS-like phenotype were screened by using whole-exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. RESULTS: A de novo heterozygous frameshift mutation of TNF-α-induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor κB pathway, was identified in one of the patients exhibiting the ALPS-like phenotype. Increased activity of the nuclear factor κB pathway was associated with haploinsufficiency of TNFAIP3 (A20). CONCLUSION: Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.

Poly (ADP-ribose) polymerase inhibitors selectively induce cytotoxicity in TCF3-HLF-positive leukemic cells.

Poly (ADP-ribose) polymerase (PARP) is an indispensable component of the DNA repair machinery. PARP inhibitors are used as cutting-edge treatments for patients with homologous recombination repair (HRR)-defective breast cancers harboring mutations in BRCA1 or BRCA2. Other tumors defective in HRR, including some hematological malignancies, are predicted to be good candidates for treatment with PARP inhibitors. Screening of leukemia-derived cell lines revealed that lymphoid lineage-derived leukemia cell lines, except for those derived from mature B cells and KMT2A (MLL)-rearranged B-cell precursors, were relatively sensitive to PARP inhibitors. By contrast, acute myelogenous leukemia cell lines, except for RUNX1-RUNXT1 (AML1-ETO)-positive lines, were relatively resistant. Intriguingly, TCF3 (E2A)-HLF-positive leukemia was sensitive to PARP inhibitors. TCF3-HLF expression suppressed HRR activity, suggesting that PARP inhibitor treatment induced synthetic lethality. Furthermore, TCF3-HLF expression decreased levels of MCPH1, which regulates the expression of BRCA1, resulting in attenuation of HRR activity. The PARP inhibitor olaparib was also effective in an in vivo xenograft model. Our results suggest a novel therapeutic approach for treating refractory leukemia, particularly the TCF3-HLF-positive subtype.

Synchronous Type 1 Papillary Renal Cell Carcinoma in a Patient with Rectal Adenocarcinoma.

Synchronous colorectal cancer (CRC) and renal cell carcinoma (RCC) is relatively rare, particularly when the synchronous RCC is of papillary subtype, which is exceedingly rare. We report a case of a 63-year-old Caucasian man with synchronous CRC and type 1 papillary RCC. After the patient presented with three episodes of melena, colonoscopy followed by biopsy confirmed rectal adenocarcinoma. The computed tomographic imaging also showed an incidental mass of the upper pole of the left kidney suspicious for RCC. Once chemoradiation therapy was successfully completed, an ultra low anterior resection and partial nephrectomy were performed concurrently. Histological examination showed colorectal adenocarcinoma (ypT1 N0 Mx) and papillary RCC type I (pT1a Nx Mx). Although the exact pathogenesis of synchronous CRC and RCC is unknown, it has been suggested that almost all patients with this entity do not have Lynch syndrome. The majority of these patients usually present with CRC-related symptoms and then, during workup, are subsequently found to have an incidental renal mass that is most often diagnosed as clear cell subtype of RCC. To the best of our knowledge, this is only the second reported case of synchronous CRC and type 1 papillary RCC.

Comprehensive Glycomics of a Multistep Human Brain Tumor Model Reveals Specific Glycosylation Patterns Related to Malignancy.

Cancer cells frequently express glycans at different levels and/or with fundamentally different structures from those expressed by normal cells, and therefore elucidation and manipulation of these glycosylations may provide a beneficial approach to cancer therapy. However, the relationship between altered glycosylation and causal genetic alteration(s) is only partially understood. Here, we employed a unique approach that applies comprehensive glycomic analysis to a previously described multistep tumorigenesis model. Normal human astrocytes were transformed via the serial introduction of hTERT, SV40ER, H-RasV12, and myrAKT, thereby mimicking human brain tumor grades I-IV. More than 160 glycans derived from three major classes of cell surface glycoconjugates (N- and O-glycans on glycoproteins, and glycosphingolipids) were quantitatively explored, and specific glycosylation patterns related to malignancy were systematically identified. The sequential introduction of hTERT, SV40ER, H-RasV12, and myrAKT led to (i) temporal expression of pauci-mannose/mono-antennary type N-glycans and GD3 (hTERT); (ii) switching from ganglio- to globo-series glycosphingolipids and the appearance of Neu5Gc (hTERT and SV40ER); (iii) temporal expression of bisecting GlcNAc residues, α2,6-sialylation, and stage-specific embryonic antigen-4, accompanied by suppression of core 2 O-glycan biosynthesis (hTERT, SV40ER and Ras); and (iv) increased expression of (neo)lacto-series glycosphingolipids and fucosylated N-glycans (hTERT, SV40ER, Ras and AKT). These sequential and transient glycomic alterations may be useful for tumor grade diagnosis and tumor prognosis, and also for the prediction of treatment response.