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Melanoma stem cells (MSCs) are characterized by their unique cell surface proteins and aberrant signaling pathways. These stemness properties are either in a causal or consequential relationship to melanoma progression, treatment resistance and recurrence. The functional analysis of CD133+ and CD133− cells in vitro and in vivo revealed that melanoma progression and treatment resistance are the consequences of CD133 signal to PI3K pathway. CD133 signal to PI3K pathway drives two downstream pathways, the PI3K/Akt/MDM2 and the PI3K/Akt/MKP-1 pathways. Activation of PI3K/Akt/MDM2 pathway results in the destabilization of p53 protein, while the activation of PI3K/Akt/MKP-1 pathway results in the inhibition of mitogen-activated protein kinases (MAPKs) JNK and p38. Activation of both pathways leads to the inhibition of fotemustine-induced apoptosis. Thus, the disruption of CD133 signal to PI3K pathway is essential to overcome Melanoma resistance to fotemustine. The pre-clinical verification of in vitro data using xenograft mouse model of MSCs confirmed the clinical relevance of CD133 signal as a therapeutic target for melanoma treatment. In conclusion, our study provides an insight into the mechanisms regulating MSCs growth and chemo-resistance and suggested a clinically relevant approach for melanoma treatment.

Abstract Background Acute kidney injury is common in patients with COVID-19, however mechanisms of kidney injury remain unclear. Since cytokine storm is likely a cause of AKI and glomerular disease, we investigated the two major transcription factors, STAT3 and NF-kB, which are known to be activated by cytokines. Methods This is an observational study of the postmortem kidneys of 50 patients who died with COVID-19 in the Mount Sinai Hospital during the first pandemic surge. All samples were reviewed under light microscopy, electron microscopy, and immunofluorescence by trained renal pathologists. In situ hybridization evaluation for SARS-CoV-2 and immunostaining of transcription factors STAT3 and NF-kB were performed. Results Consistent with previous findings, acute tubular injury was the major pathological finding, together with global or focal glomerulosclerosis. We were not able to detect SARS-CoV-2 in kidney cells. ACE2 expression was reduced in the tubular cells of patients who died with COVID-19 and did not co-localize with TMPRSS2. SARS-CoV-2 was identified occasionally in the mononuclear cells in the peritubular capillary and interstitium. STAT3 phosphorylation at Tyr705 was increased in 2 cases in the glomeruli and in 3 cases in the tubulointerstitial compartments. Interestingly, STAT3 phosphorylation at Ser727 increased in 9 cases but only in the tubulointerstitial compartment. A significant increase in NF-kB phosphorylation at Ser276 was also found in the tubulointerstitium of the two patients with increased p-STAT3 (Tyr705). Conclusions Our findings suggest that, instead of tyrosine phosphorylation, serine phosphorylation of STAT3 is commonly activated in the kidney of patients with COVID-19.

Myocyte enhancer-binding factor 2B (MEF2B) has been implicated as a transcriptional regulator for BCL6. However, details about the interaction between MEF2B and BCL6 during expression, as well as the relationship of MEF2B to the expression of other germinal center (GC) markers, have not yet been fully explained. Using germinal center B-cell-like diffuse large B-cell lymphoma (GC-DLBCL) and activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines, we analyzed the expression of MEF2B and its associations with BCL6, CD10, and ERK. Furthermore, small interfering RNA (siRNA) was used to study the possible effects of MEF2B knockdown on these proteins and cell growth. Analysis of the BCL6 transcriptional complex was performed using electrophoretic mobility shift assay. The correlation between MEF2B expression and the genetic type of DLBCL was assessed using immunohistochemistry on 111 patient samples, and via in silico analysis of publicly available microarray (Gene Expression Omnibus (GEO)) datasets. Our results indicate that the expression of MEF2B protein is important for the growth of GC-DLBCL cells, as evidenced by MEF2B knockdown inhibition of cell growth and the subsequent suppression of BCL6, CD10, and ERK phosphorylation. Analysis of BCL6 transcription factors in nuclear extracts of MEF2-expressing DLBCL cells showed involvement of MEF2B with AP-2α and BCL6 proteins in the formation of the BCL6 gene transcriptional complex. Indeed, differential expression of MEF2B in the GC-DLBCL is statistically significant compared to the ABC-DLBCL in the GEO datasets, as well as in tissue microarray, as indicated via immunohistochemistry (Visco–Young algorithm). Our findings indicate that MEF2B is an essential component of the BCL6 gene transcriptional complex for the regulation of DLBCL growth via the promotion of BCL6 expression. Beyond its regulatory role in DLBCL growth, MEF2B expression correlated positively with BCL6 and CD10 expression, and was preferentially expressed in the GBC-DLBCL group.

Genetics has played an important role in risk stratification for plasma cell myeloma patients, providing therapeutic guidance. In this study, we investigated the correlation of bone marrow morphologic features and genetic aberrations, including gene expression profiles, translocations, and gene mutations. For the first time we show that high plasma cell volume, diffuse sheet growth pattern, immature cell morphology, high mitotic index, and increased reticulin fibrosis, significantly correlates with high risk disease determined by MyPRS gene expression profiles. Furthermore, we show the association between MyPRS risk stratification and chromosomal alterations and specific gene mutations. We also demonstrate the combinational effect of TP53 mutation and 17p loss on the histological changes in bone marrow.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Background Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells. Interferon gamma (IFNγ) is one of the common cytokines coordinating tumor immune response and the associated biological consequences. Although the role of IFNγ in the modulation of tumor immunity has been widely documented, the mechanisms regulating IFNγ-induced cell death, during the course of immune therapy, is not described in detail. Results IFNγ triggered apoptosis of CLS-354 and RPMI 2650 cells, enhanced the protein expression and activation of indoleamine 2,3-dioxygenase (IDO), and suppressed the basal expression of heme oxygenase-1(HO-1). Interestingly, IFNγ induced the loss of mitochondrial membrane potential (Δ ψ m) and increased accumulation of reactive oxygen species (ROS). The cytokine also induced the activation of Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT)1, apoptosis signal-regulating kinase 1 (ASK1), p38, c-jun-N-terminal kinase (JNK) and NF-κB pathways and the transcription factors STAT1, interferon regulatory factor 1 (IRF1), AP-1, ATF-2, NF-κB and p53, and expression of Noxa protein. Furthermore, IFNγ was found to trigger endoplasmic reticulum (ER) stress as evidenced by the cleavage of caspase-4 and activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring-1α (IRE1α) pathways. Using specific inhibitors, we identified a potential role for IDO as apoptotic mediator in the regulation of IFNγ-induced apoptosis of head and neck squamous cell carcinoma (HNSCC) cells via Noxa-mediated mitochondrial dysregulation and ER stress. Conclusion In addition to the elucidation of the role of IDO in the modulation of apoptosis, our study provides new insights into the molecular mechanisms of IFNγ-induced apoptosis of HNSCC cells during the course of immune therapy.

Prostate cancer (PCa) accounts for roughly 15% of diagnosed cancers among men, with disease incidence increasing worldwide. Age, family history and ethnicity, diet, physical activity, and chemoprevention all play a role in reducing PCa risk. The prostate is an exocrine gland that is characterized by its multi-functionality, being involved in reproductive aspects such as male ejaculation and orgasmic ecstasy, as well as playing key roles in the regulation of local and systemic concentrations of 5α-dihydrotestosterone. The increase in androgen receptors at the ventral prostate is the first elevated response induced by copulation. The regulation of prostate growth and function is mediated by an androgen-dependent mechanism. Binding 5-DHT to androgen receptors (AR) results in the formation of a 5α-DHT:AR complex. The interaction of the 5α-DHT:AR complex with the specific DNA enhancer element of androgen-regulated genes leads to the regulation of androgen-specific target genes to maintain prostate homeostasis. Consequently, ejaculation may play a significant role in the reduction of PCa risk. Thus, frequent ejaculation in the absence of risky sexual behavior is a possible approach for the prevention of PCa. In this review, we provide an insight into possible mechanisms regulating the impact of frequent ejaculation on reducing PCa risk.

A rare case of acquired amegakaryocytic thrombocytopenia (AATP) in a 35-year-old woman who presented with anaemia and thrombocytopenia at 22 weeks gestation. The first diagnostic impression was of an evolving aplastic anaemia; however, the patient was simultaneously diagnosed with severe vitamin B12 deficiency in the setting of vegetarianism. Once the cyanocobalamin deficiency was corrected, a repeat bone marrow biopsy revealed an isolated depletion of megakaryocytes, which suggested the diagnosis of AATP. Supportive care was provided for her anaemia and thrombocytopenia and she delivered a healthy baby girl with a normal platelet count. The patient was subsequently started on romiplostim with steady improvement in her platelet counts. This rare AATP case presentation highlights the importance of a well-structured diagnostic approach to thrombocytopenia during pregnancy and supports the successful use of thrombopoietin agonists for the management of AATP.

Meningiomas in the pediatric population are uncommon primary brain tumors, and rhabdoid meningiomas are exceedingly rare. We describe herein a 16-year-old female who presented with a giant frontal mass with intracranial and extracranial components. Histologic, immunohistochemical, and ultrastructural examinations showed the intracranial tumor to be rhabdoid meningioma, and the extracranial tumor was meningothelial meningioma. Cytogenetic study of the intracranial tumor showed monosomy 22, and the extracranial tumor showed allelic losses at 18p11.32. Because of the different cytogenetic findings and the absence of communication between these two tumors, we concluded that these tumors were separate and represent colliding meningiomas. Furthermore, the rhabdoid meningioma lacked obvious histologic evidence of malignancy. The presence of colliding meningiomas with different cytogenetic abnormalities as well as a rhabdoid meningioma showing no conspicuous evidence of malignancy have not been reported in children before.