Cryptococcus neoformans infections are more common among immunosuppressed individuals, causing the most widespread opportunistic CNS infection among HIV-positive patients . Specifically, those with cellular immunosuppression, such as patients with HIV positive CD4 counts less than 100. When a patient presents with atypical symptoms, it can be difficult to diagnose due to its infrequent presentation in HIV negative patients. Due to the rarity of encounters in HIV-negative patients, when atypical symptoms are present, it poses a diagnostic challenge. Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin B-cell lymphoma that is known to be associated with cellular immunosuppression . This demonstrates the need for early diagnosis and recognition of cryptococcal infections and as a physician should be vigilant to diagnose cryptococcal who is on Acalabrutinib with MCL . CLL patients receiving ibrutinib should be evaluated for cryptococcal infection, which is potentially life threatening if overlooked . Meningitis caused by Cryptococcus mainly presents with fever and altered mental status but in this case, our patient 78-year-old male with mantle cell lymphoma, undergoing a regimen of Rituximab-Bendamustine (BR) in combination with acalabrutinib (TKI), presented with hypotension to ED in June 2021. Cryptococcal infection in patient receiving ibrutinib were mostly reported in patients with Chronic lymphocytic leukemia, who have poor immune reconstitution. Here we are reporting case of cryptococcal meningoencephalitis in patient with MCL on acalabrutinib which is never reported before.
B-cell lymphoma 2 (Bcl-2)-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that modulates major biological processes, including apoptosis, autophagy, and development to promote cellular adaptive responses to stress stimuli. Although BAG3 is constitutively expressed in several cell types, its expression is also inducible and is regulated by microRNAs (miRNAs). miRNAs are small non-coding RNAs that mostly bind to the 3′-UTR (untranslated region) of mRNAs to inhibit their translation or to promote their degradation. miRNAs can potentially regulate over 50% of the protein-coding genes in a cell and therefore are involved in the regulation of all major functions, including cell differentiation, growth, proliferation, apoptosis, and autophagy. Dysregulation of miRNA expression is associated with pathogenesis of numerous diseases, including peripheral artery disease (PAD). BAG3 plays a critical role in regulating the response of skeletal muscle cells to ischemia by its ability to regulate autophagy. However, the biological role of miRNAs in the regulation of BAG3 in biological processes has only been elucidated recently. In this review, we discuss how miRNA may play a key role in regulating BAG3 expression under normal and pathological conditions.
Human telomerase is a specialized DNA polymerase whose catalytic core includes both TERT and human telomerase RNA (hTR). Telomerase in humans, which is silent in most somatic cells, is activated to maintain the telomere length (TEL) in various types of cancer cells, including melanoma. In the vast majority of tumor cells, the TERT promoter is mutated to promote proliferation and inhibit apoptosis. Here, we exploited NG-ABEmax to revert TERT -146 T to -146 C in melanoma, and successfully obtained TERT promoter revertant mutant cells. These TERT revertant mutant cells exhibited significant growth inhibition both in vitro and in vivo. Moreover, A375−146C/C cells exhibited telomere shortening and the downregulation of TERT at both the transcription and protein levels, and migration and invasion were inhibited. In addition, TERT promoter revertant mutation abrogated the inhibitory effect of mutant TERT on apoptosis via B-cell lymphoma 2 (Blc-2), ultimately leading to cell death. Collectively, the results of our work demonstrate that reverting mutations in the TERT promoter is a potential therapeutic option for melanoma.
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) and primary cutaneous follicle center lymphoma with a diffuse population of large cells (PCFCL-LC) are both primary cutaneous B-cell lymphomas with large-cell morphology (CLBCL) but with different clinical characteristics and behavior. In systemic diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), gene-expression profiling (GEP) revealed two molecular subgroups based on their cell-of-origin (COO) with prognostic significance: the germinal center B-cell-like (GCB) subtype and the activated B-cell-like (ABC) subtype. This study investigated whether COO classification is a useful tool for classification of CLBCL. For this retrospective study, 51 patients with PCDLBCL-LT and 15 patients with PCFCL-LC were analyzed for their COO according to the immunohistochemistry-based Hans algorithm and the NanoString GEP-based Lymph2Cx algorithm. In PCFCL-LC, all cases (100%) classified as GCB by both Hans and Lymph2Cx. In contrast, COO classification in PCDLBCL-LT was heterogeneous. Using Hans, 75% of the PCDLBCL-LT patients classified as non-GCB and 25% as GCB, while Lymph2Cx classified only 18% as ABC, 43% as unclassified/intermediate, and 39% as GCB. These COO subgroups did not differ in the expression of BCL2 and IgM, mutations in MYD88 and/or CD79B, loss of CDKN2A, or survival. In conclusion, PCFCL-LC uniformly classified as GCB, while PCDLBCL-LT classified along the COO spectrum of DLBCL-NOS using the Hans and Lymph2Cx algorithms. In contrast to DLBCL-NOS, the clinical relevance of COO classification in CLBCL using these algorithms has limitations and cannot be used as an alternative for the current multiparameter approach in differentiation of PCDLBCL-LT and PCFCL-LC.
No head-to-head trials have compared the efficacy of tisagenlecleucel versus historical treatments for adults with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This study indirectly compared the overall survival (OS) and overall response rate (ORR) associated with tisagenlecleucel, using data from the JULIET study (NCT02445248), versus historical treatments assessed in the CORAL study follow-up population. To assess treatment effects in the treated (full analysis set [FAS]) and enrolled (intent-to-treat [ITT]) study populations, the JULIET FAS vs. the CORAL follow-up FAS and JULIET ITT vs. CORAL follow-up ITT populations were separately compared. Propensity score weighting using standardized mortality ratio weight (SMRW) and fine stratification weight (FSW) was used to compare OS and ORR, adjusting for baseline confounders. The results indicated that tisagenlecleucel was associated with a lower hazard of death among the FAS (adjusted hazard ratio [95% CI], both FSW and SMRW: 0.44 [0.32, 0.59]) and ITT populations (FSW: 0.60 [0.44, 0.77], SMRW: 0.57 [0.44, 0.73]; all p<0.001). Median OS was 12.48 months (JULIET) vs. 4.34-4.40 months (CORAL) for the FAS, and 8.25 (JULIET) vs. 4.04-4.86 (CORAL) for the ITT populations. Tisagenlecleucel was associated with a significantly higher ORR compared to historical treatments among the FAS (adjusted response rate difference [95% CI], both FSW and SMRW: 36% [22%, 0.48%]; p<0.001) and among the ITT populations after SMRW adjustment (11% [0%, 22%]; p=0.043). This analysis supports that improved response and OS are achieved in r/r DLBCL patients treated with tisagenlecleucel when compared to those treated with alternative historical treatments.