Concurrent Breast Carcinoma and Follicular Lymphoma: A Case Series.

BACKGROUND The incidence of multiple primaries in cancer patients is 2-17%. However, the synchronous co-occurrence of adenocarcinoma of the breast and follicular lymphoma is rare. CASE REPORT We describe a case series of 3 post-menopausal women who presented to our institute with a breast lump. On further investigations, 2 of them had invasive ductal carcinoma and 1 had invasive lobular carcinoma of the breast. All 3 cancers were estrogen/progesterone receptor (ER/PR)-positive and human epidermal growth factor receptor 2 (HER-2)-negative. During the staging PET scans, all 3 patients had increased FDG uptake in axillary, mesenteric, and inguinal lymph nodes, respectively, raising concerns for metastatic disease. However, subsequent biopsies revealed them as follicular lymphomas occurring as a second concurrent primary malignancy. All patients underwent radical mastectomies with sentinel lymph node dissection followed by chemotherapy and hormonal therapy. Most of the lymphomas were low grade, which the oncologist closely followed. CONCLUSIONS Very few cases of breast cancer and follicular lymphoma co-occur; this is not limited to the axillary lymph nodes and can occur in any part of the lymphatic chain. Regional lymph node enlargement detected on examination or imaging does not always indicate metastasis. A high index of suspicion is needed followed by lymph node biopsy to rule out any second primary malignancy.

A 31-Year-Old Man with COVID-19-Associated Empyema and Lupus Anticoagulant.

BACKGROUND COVID-19 was declared a pandemic in March 2020 in the United States. It has been associated with high mortality and morbidity all over the world. COVID-19 can cause a significant inflammatory response leading to coagulopathy and this hypercoagulable state has been associated with worse clinical outcomes in these patients. The published data regarding the presence of lupus anticoagulant in critically ill COVID-19-positive patients is limited and indicates varying conclusions so far. CASE REPORT Here, we present a case of a 31-year-old man who was admitted to the hospital with COVID-19 pneumonia, complicated with superadded bacterial empyema and required video-assisted thoracoscopic surgery with decortication. This patient also had prolonged prothrombin time on preoperative labs, which was not corrected with mixing study. Further workup detected positive lupus anticoagulant and anti-cardiolipin IgM along with alteration in other coagulation factor levels. The patient was treated with fresh frozen plasma and vitamin K before surgical intervention. He had an uneventful surgical course. He received prophylactic-dose low molecular weight heparin for venous thromboembolism prophylaxis and did not experience any thrombotic events while hospitalized. CONCLUSIONS COVID-19 infection creates a prothrombotic state in affected patients. The formation of micro-thrombotic emboli results in significantly increased mortality and morbidity. Routine anticoagulation with low molecular weight heparin can prevent thrombotic events and thus can improve patient outcomes. In patients with elevated prothrombin time, lupus anticoagulant/anti-cardiolipin antibody-positivity should be suspected, and anticoagulation prophylaxis should be continued perioperatively for better outcomes.

Integrating systemic and surgical approaches to treating metastatic colorectal cancer.

Multiple new treatment options for metastatic colorectal cancer have been developed over the past 2 decades, including conventional chemotherapy and agents directed against vascular endothelial growth factor and epidermal growth factor receptor. Combination regimens, integrated with surgical approaches, have led to an increase in median survival, and a minority of patients with resectable disease can survive for years. Clinical decision-making therefore requires a strategic, biomarker-based multidisciplinary approach to maximize life expectancy and quality of life. This review describes systemic approaches to the treatment of patients with metastatic colorectal cancer, including integration with liver resection, other liver-directed therapies, and primary resection.

Unusual Course of Splenic Marginal Zone Lymphoma.

A 53-year-old woman was diagnosed with splenic marginal zone lymphoma by pathological examination on left submandibular lymph node and bone marrow biopsies and markedly enlarged spleen. Four cycles of Rituximab chemotherapy were given. Seven months after finishing Rituximab chemotherapy, she developed left upper extremity swelling without evidence of deep venous thrombosis. Repeat PET/CT scan demonstrated multiple left axillary lymph nodes extending to left retroclavicular region and a new lymph node posterior to the left scapula. Biopsy of the lymph node demonstrated marginal zone lymhoma pattern with increased numbers of large cells, but not outright diffuse large B-cell lymphoma. Despite resuming rituximab, patient had persistent leukocytosis and severe anemia. Restaging PET/CT showed 3 new left anterior cervical lymph nodes and 1 new right axillary lymph node. Spleen has further enlarged. R-CHOP chemotherapy was started, which improved leukocytosis.After 4 cycles of R-CHOP, PET/CT showed new metabolic activity within right inguinal and abdominal lymph nodes. Patient was given one cycle of Bendamustine. She developed a possible "hematoma" in right medial elbow. However, MRI study revealed a subcutaneous deposit of the lymphoma. Patient needs consistently blood transfusion and she deteriorated quickly. Our patient had an aggressive course of splenic marginal zone lymphoma, not responding to four trials of chemotherapy although SMZL is well-known to be an indolent low grade lymphoma. This case report emphasizes the importance to individualize the treatment in SMZL patients and repeat bone marrow biopsy if the disease recurs.

Phosphorylation of PPP(S/T)P motif of the free LRP6 intracellular domain is not required to activate the Wnt/beta-catenin pathway and attenuate GSK3beta activity.

The canonical Wnt/beta-catenin signaling pathway plays a critical role in numerous physiological and pathological processes. LRP6 is an essential co-receptor for Wnt/beta-catenin signaling; as transduction of the Wnt signal is strongly dependent upon GSK3beta-mediated phosphorylation of multiple PPP(S/T)P motifs within the membrane-anchored LRP6 intracellular domain. Previously, we showed that the free LRP6 intracellular domain (LRP6-ICD) can activate the Wnt/beta-catenin pathway in a beta-catenin and TCF/LEF-1 dependent manner, as well as interact with and attenuate GSK3beta activity. However, it is unknown if the ability of LRP6-ICD to attenuate GSK3beta activity and modulate activation of the Wnt/beta-catenin pathway requires phosphorylation of the LRP6-ICD PPP(S/T)P motifs, in a manner similar to the membrane-anchored LRP6 intracellular domain. Here we provide evidence that the LRP6-ICD does not have to be phosphorylated at its PPP(S/T)P motif by GSK3beta to stabilize endogenous cytosolic beta-catenin resulting in activation of TCF/LEF-1 and the Wnt/beta-catenin pathway. LRP6-ICD and a mutant in which all 5 PPP(S/T)P motifs were changed to PPP(A)P motifs equivalently interacted with and attenuated GSK3beta activity in vitro, and both constructs inhibited the in situ GSK3beta-mediated phosphorylation of beta-catenin and tau to the same extent. These data indicate that the LRP6-ICD attenuates GSK3beta activity similar to other GSK3beta binding proteins, and is not a result of it being a GSK3beta substrate. Our findings suggest the functional and regulatory mechanisms governing the free LRP6-ICD may be distinct from membrane-anchored LRP6, and that release of the LRP6-ICD may provide a complimentary signaling cascade capable of modulating Wnt-dependent gene expression.

Regulated proteolytic processing of LRP6 results in release of its intracellular domain.

Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of low-density lipoprotein receptor (LDLR) family which cooperates with Frizzled receptors to transduce the canonical Wnt signal. As a critical component of the canonical Wnt pathway, LRP6 is essential for appropriate brain development, however, the mechanism by which LRP6 facilitates Wnt canonical signaling has not been fully elucidated. Interestingly, LRP6 which lacks its extracellular domain can constitutively activate TCF/LEF and potentiate the Wnt signal. Further, the free cytosolic tail of LRP6 interacts directly with glycogen synthase kinase (GSK3) and inhibits GSK3's activity in the Wnt canonical pathway which results in increased TCF/LEF activation. However, whether these truncated forms of LRP6 are physiologically relevant is unclear. Recent studies have shown that other members of the LDLR family undergo gamma-secretase dependent regulated intramembrane proteolysis (RIP). Using independent experimental approaches, we show that LRP6 also undergoes RIP. The extracellular domain of LRP6 is shed and released into the surrounding milieu and the cytoplasmic tail is cleaved by gamma-secretase-like activity to release the intracellular domain. Furthermore, protein kinase C, Wnt 3a and Dickkopf-1 modulate this process. These findings suggest a novel mechanism for LRP6 in Wnt signaling: induction of ectodomain shedding of LRP6, followed by the gamma-secretase involved proteolytic releasing its intracellular domain (ICD) which then binds to GSK3 inhibiting its activity and thus activates the canonical Wnt signaling pathway.

The role of tau phosphorylation in the pathogenesis of Alzheimer's disease.

The microtubule-associated protein tau, which is abundantly expressed in neurons, is deposited in cells in an abnormally phosphorylated state as fibrillar lesions in numerous neurodegenerative diseases, with the most notable being Alzheimer's disease. Tau plays a crucial role in the neuron as it binds and stabilizes microtubules, and can regulate axonal transport; functions that are regulated by site-specific phosphorylation events. In pathological conditions such as Alzheimer's disease and other tauopathies, tau is abnormally phosphorylated, and that this contributes to its dysfunction. Given the increasing evidence that a disruption in the normal phosphorylation state of tau followed by conformational changes plays a key role in the pathogenic events that occur in Alzheimer's disease and other tauopathies; it is critical to elucidate the regulation of tau phosphorylation. This review focuses on recent literature pertaining to the regulation of tau phosphorylation and function, and the role that a dysregulation of tau phosphorylation may play in the neuronal dysfunction in Alzheimer's disease.

The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity.

Glycogen synthase kinase 3 (GSK3) is a widely expressed Ser/Thr protein kinase that phosphorylates numerous substrates. This large number of substrates requires precise and specific regulation of GSK3 activity, which is achieved by a combination of phosphorylation, localization, and interactions with GSK3-binding proteins. Members of the Wnt canonical pathway have been shown to influence GSK3 activity. Through a yeast two-hybrid screen, we identified the Wnt canonical pathway co-receptor protein low density lipoprotein receptor-related protein 6 (LRP6) as a GSK3-binding protein. The interaction between the C terminus of LRP6 and GSK3 was also confirmed by in vitro GST pull-down assays and in situ coimmunoprecipitation assays. In vitro assays using immunoprecipitated proteins demonstrated that the C terminus of LRP6 significantly attenuated the activity of GSK3beta. In situ, LRP6 significantly decreased GSK3beta-mediated phosphorylation of tau at both primed and unprimed sites. Finally, it was also demonstrated that GSK3beta phosphorylates the PPP(S/T)P motifs in the C terminus of LRP6. This is the first identification of a direct interaction between LRP6 and GSK3, which results in an attenuation of GSK3 activity.

Role of the intracellular domains of LRP5 and LRP6 in activating the Wnt canonical pathway.

LDL-receptor related proteins 5 and 6 (LRP5/6) are co-receptors of Frizzled receptors that mediate Wnt-induced activation of the transcription factor family TCF/LEF-1. Even though LRP5 and LRP6 are highly homologous, LRP6, but not LRP5, is expressed primarily in the nervous system and deletion of the LRP6 gene results in significant brain abnormalities, while deletion of LRP5 results in primarily decreased bone density. Additionally, the exact function of LRP5 and LRP6 have not been clearly defined, although it is clear that they both play key roles in the Wnt canonical pathway. In this study the role of the intracellular domains of LRP5/6 in mediating Wnt signaling was examined. In the absence of exogenous Wnt 3a, full-length (FL) LRP6, but not LRP5, increased TCF/LEF-1 transcriptional activity, however both significantly potentiated Wnt 3a-induced TCF/LEF-1 activation. In contrast to the findings with the FL constructs, the intracellular domains (membrane-anchored and cytosolic) of both LRP5 and LRP6 significantly increased TCF/LEF-1 activation in the absence of Wnt 3a, and potentiated the Wnt 3a-induced decrease in beta-catenin phosphorylation, increase in free beta-catenin levels and the increase in TCF/LEF-1 activity. These findings demonstrate that: (1) LRP5 and LRP6 differentially modulate TCF/LEF-1 activation in the absence of Wnt 3a and (2) the intracellular C-terminal domains of LRP5/6 potentiate Wnt 3a-induced TCF/LEF-1 activation whether or not they are membrane-anchored. These findings provide significant new insights into the roles of LRP5/6 in modulating canonical Wnt signaling.

Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: synergy with interleukin-1beta, tumor necrosis factor-alpha, and bacterial lipopolysaccharide.

Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E(2) (PGE(2)), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE(2) production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE(2) production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE(2) production by OSM and IL-1beta treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE(2) synthesis. Of the enzymes involved in PGE(2) biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1beta. Nuclear run-on assays demonstrate that OSM and IL-1beta synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1beta. To effect synergy on the PGE(2) level, OSM signals in part through its gp130/OSMRbeta receptor, since neutralizing antibodies against gp130 and OSMRbeta, but not LIFRbeta, decrease PGE(2) production in response to OSM plus IL-1beta. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1beta and OSM upregulation of COX-2 and PGE(2), indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE(2) amplification may be active in brain pathologies where both OSM and IL-1beta are present, such as glioblastomas and multiple sclerosis.

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3beta.

Glycogen synthase kinase 3beta (GSK3beta) is an essential protein kinase that regulates numerous functions within the cell. One critically important substrate of GSK3beta is the microtubule-associated protein tau. Phosphorylation of tau by GSK3beta decreases tau-microtubule interactions. In addition to phosphorylating tau, GSK3beta is a downstream regulator of the wnt signaling pathway, which maintains the levels of beta-catenin. Axin plays a central role in regulating beta-catenin levels by bringing together GSK3beta and beta-catenin and facilitating the phosphorylation of beta-catenin, targeting it for ubiquitination and degradation by the proteasome. Although axin clearly facilitates the phosphorylation of beta-catenin, its effects on the phosphorylation of other GSK3beta substrates are unclear. Therefore in this study the effects of axin on GSK3beta-mediated tau phosphorylation were examined. The results clearly demonstrate that axin is a negative regulator of tau phosphorylation by GSK3beta. This negative regulation of GSK3beta-mediated tau phosphorylation is due to the fact that axin efficiently binds GSK3beta but not tau and thus sequesters GSK3beta away from tau, as an axin mutant that does not bind GSK3beta did not inhibit tau phosphorylation by GSK3beta. This is the first demonstration that axin negatively affects the phosphorylation of a GSK3beta substrate, and provides a novel mechanism by which tau phosphorylation and function can be regulated within the cell.

[A study of human enteric nervous system development in the middle stage of embryogenesis]

OBJECTIVE: To investigate the development of the enteric nervous system(ENS) in the middle stage(the 4th approximate, equals 6th months) of human embryogenesis. METHODS: A histologic evaluation of the clonic enteric nervous system was done using NADPHd histochemistry, PAP immunohistochemistry, with anti-PGP 9.5 and anti-S-100 protein. RESULTS: During this stage of embryology three things were noted. (1)The nerves in the myenteric layer increased markedly. This was shown by the PGP 9.5 immunoreactive nerves spreading out and the S-100 protein immunoreactive nerves forming a "bamboo basket"pattern. (2)The whole myenteric colon showed nitrigeric nerves paralleling the growth of the myofibers in the circular muscle layer. Nitrigeric perikara were rarely found in the extrinsic submucosal layer.(3) In the whole-mounted preparations reactive nerves formed the complex nerve net in the myenteric layer. CONCLUSION: The middle stage of embryogensis is very important to the development of the colon ENS.