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Cellular miRNA-31 and miRNA-125b as predictors of remission and major disease improvement in patients with early rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease that impairs quality of life, highlighting the need for novel biomarkers for early diagnosis and improve disease management. This study explored the cellular microRNAs (miRNAs) profile in early RA to identify potential predictors of therapeutic response. We measured a panel of 768 miRNAs in peripheral blood mononuclear cells (PBMCs) from two early RA cohorts (< 6 months), stratified by sustained SDAI/CDAI remission and non-response to conventional therapy over 12 months. Initial screening identified 13 differentially expressed miRNAs (≥ 1.5-fo

Структура-ориентированное исследование ДНК-аптамера, целевого PTK7, выявляет сложную 3D-составляющую, направляющую оптимизацию функции.

DNA аптамеры вышли в качестве новых молекулярных инструментов в терапевтической и диагностической медицине благодаря своей высокой аффинности и специфичности к белковым целям, что определяется их способностью сворачиваться в отличительные трехмерные (3D) структуры. Однако при проектировании и моделировании аптамеров часто игнорируются тонкие атомные взаимодействия, формирующие 3D структуры, что приводит к неэффективной оптимизации функциональных свойств. Проблемы сохраняются при определении высокоразрешающих структур комплексов аптамер-белок. Кроме того, экспериментально определенные 3D структ

Identification of a 4-lncRNA signature predicting prognosis of patients with non-small cell lung cancer: a multicenter study in China.

BackgroundPrevious findings have indicated that the tumor, nodes, and metastases (TNM) staging system is not sufficient to accurately predict survival outcomes in patients with non-small lung carcinoma (NSCLC). Thus, this study aims to identify a long non-coding RNA (lncRNA) signature for predicting survival in patients with NSCLC and to provide additional prognostic information to TNM staging system.MethodsPatients with NSCLC were recruited from a hospital and divided into a discovery cohort (n = 194) and validation cohort (n = 172), and detected using a custom lncRNA microarray. Another 73 N

Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect.

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high propensity for lymphatic spread and distant metastasis. It is prominent as an endemic malignancy in Southern China and Southeast Asia regions. Studies on NPC pathogenesis mechanism in the past decades such as through Epstein Barr Virus (EBV) infection and oncogenic molecular aberrations have explored several potential targets for therapy and diagnosis. The EBV infection introduces oncoviral proteins that consequently hyperactivate many promitotic pathways and block cell-death inducers. EBV infection is so prevalent in NPC pat

MicroRNAs and Chinese Medicinal Herbs: New Possibilities in Cancer Therapy.

In recent decades Chinese medicine has been used worldwide as a complementary and alternative medicine to treat cancer. Plenty of studies have shown that microRNAs (miRNAs) play fundamental roles in many pathological processes, including cancer, while the anti-cancer mechanisms of Chinese medicinal herbs targeting miRNAs also have been extensively explored. Our previous studies and those of others on Chinese medicinal herbs and miRNAs in various cancer models have provided a possibility of new cancer therapies, for example, up-regulating the expression of miR-23a may activate the positive regu

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… They have been shown to be involved in RNA silencing and regulation of the expression of target genes by attaching to the 3′ untranslated region (3′ UTR) of target mRNAs. miRNAs are usually transcribed by RNA polymerase II from their own genes or from introns [ 4 , 5 ]. …

Functional Investigation of IGF1R Mutations in Multiple Myeloma.

High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact of IGF1R mutations is so far unknown, we investigated the functional impact of IGF1R mutations on survival signaling, viability/proliferation and survival response to therapy. We transfe

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications.

Cancer is one of the most frequently diagnosed malignant diseases worldwide, posing a serious, long-term threat to patients' health and life. Systemic chemotherapy remains the first-line therapeutic approach for recurrent or metastatic cancer patients after surgery, with the potential to effectively extend patient survival. However, the development of drug resistance seriously limits the clinical efficiency of chemotherapy and ultimately results in treatment failure and patient death. A large number of studies have shown that non-coding RNAs (ncRNAs), particularly microRNAs, long non-coding RN

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… For instance, both miRNAs and lncRNAs are transcribed by RNA polymerase II (Pol II) from genomic loci. Primary miRNAs (pri-miRNAs) are subsequently catalyzed by a microprocessor complex consisting of DiGeorge syndrome critical region 8 (DGCR8) and Drosha to generate precursor miRNAs (pre-miRNAs). … (B) LncRNA transcribed by RNA polymerase II is exported to the cytoplasm. Subsequently, lncRNA exerts its biological role by acting as sponges of miRNAs, RBPs, and TFs. …

C-type natriuretic peptide in combination with sildenafil attenuates proliferation of rhabdomyosarcoma cells.

Rhabdomyosarcoma (RMS) is a malignant mesenchymal tumor and the most common soft tissue sarcoma in children. Because of several complications associated with intensive multimodal therapies, including growth disturbance and secondary cancer, novel therapies with less toxicity are urgently needed. C-type natriuretic peptide (CNP), an endogenous peptide secreted by endothelial cells, exerts antiproliferative effects in multiple types of mesenchymal cells. Therefore, we investigated whether CNP attenuates proliferation of RMS cells. We examined RMS patient samples and RMS cell lines. All RMS clini

The New Therapeutic Strategies in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10-15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization of T-ALL, but there are currently no genetic prognostic markers. Despite chemotherapy regimens, steroids, and allogeneic transplantation, relapse is the main problem in children with T-ALL. Due to the development of high-throughput molecular methods, the ability to defin

Biological Roles and Mechanisms of Circular RNA in Human Cancers.

Circular RNA (circRNA) is an intriguing class of RNA with covalently closed-loop structure and is highly stable and conservative. As new members of the ncRNAs, the function, mechanism, potential diagnostic biomarker, and therapeutic target have raised increased attention. Most circRNAs are presented with characteristics of abundance, stability, conservatism, and often exhibiting tissue/developmental-stage-specific manner. Over 30,000 circRNAs have been identified with their unique structures to maintain stability more easily than linear RNAs. An increased numbers of circRNAs are dysregulated a

Novel_circ_003686 regulates the osteogenic differentiation of MSCs in patients with myeloma bone disease through miR-142-5p/IGF1 axis.

ObjectivesCirc_003686 is a novel_circRNA with abnormally low expression found in the samples of multiple myeloma bone disease (MBD) patients. The current research intended to investigate the effects of novel_circ_003686 in osteogenesis-induced differentiation of bone marrow mesenchymal stem cells (BMSCs) in MBD.MethodsBMSCs were extracted from MBD patients and normal participants, the pcDNA3.1 encoding the circ_003686 (ov-circ_003686), miR-142-5p-mimic/inhibitor and siRNA oligonucleotides targeting insulin like growth factor 1 (IGF1, si-IGF1) were applied to intervene circ_003686, miR-142-5p a

Current State of Knowledge on Primary Sjögren's Syndrome, an Autoimmune Exocrinopathy.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune rheumatic disease characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands, whereby sicca syndrome and/or systemic manifestations are the clinical hallmarks, associated with a particular autoantibody profile. pSS is the most frequent connective tissue disease after rheumatoid arthritis, affecting 0.3-3% of the population. Women are more prone to develop pSS than men, with a sex ratio of 9:1. Considered in the past as innocent collateral passive victims of autoimmunity, the epithelial cells of the saliv

Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling.

Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes sha

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… CBP and p300 are histone acetyltransferases that enhance the ability of CREB to activate transcription by relaxing the chromatin structure at gene promoter regions and creating scaffolds for recruitment of RNA polymerase II complexes to the promoter. … Active P-TEFb is a crucial regulator for stimulating RNA polymerase II elongation. About half of P-TEFb associates with 7SK snRNA and HEXIM1 to form an inactive P-TEFb/HEXIM1/7SK snRNP complex. …

A Pathology Experience of Posttransplant Lymphoproliferative Disorder From One Tertiary Hospital: Pathology Concepts and Diagnostic Approach.

BACKGROUND: Solid organ transplantation and bone marrow/hematologic stem cell transplantation recipients face a heightened risk of developing malignancies or cancer as a result of immunosuppression. Posttransplant lymphoproliferative disorders (PTLD) are a range of disorders from benign lymphoid growth to lymphoma found post-transplant. Risk factors for PTLD include high immunosuppressive use and oncogenic effects of Epstein-Barr virus (EBV). There is a lack of comprehensive clinical and pathological documentation of PTLD cases among Saudi patients, and the available data are limited to a few

pIL6-TRAIL-engineered umbilical cord mesenchymal/stromal stem cells are highly cytotoxic for myeloma cells both in vitro and in vivo.

BackgroundMesenchymal/stromal stem cells (MSCs) are favorably regarded in anti-cancer cytotherapies for their spontaneous chemotaxis toward inflammatory and tumor environments associated with an intrinsic cytotoxicity against tumor cells. Placenta-derived or TRAIL-engineered adipose MSCs have been shown to exert anti-tumor activity in both in-vitro and in-vivo models of multiple myeloma (MM) while TRAIL-transduced umbilical cord (UC)-MSCs appear efficient inducers of apoptosis in a few solid tumors. However, apoptosis is not selective for cancer cells since specific TRAIL receptors are also ex

DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma.

Aberrant DNA methylation plays a relevant role in multiple myeloma (MM) pathogenesis. MicroRNAs (miRNAs) are a class of small non-coding RNAs that recently emerged as master regulator of gene expression by targeting protein-coding mRNAs. However, miRNAs involvement in the regulation of the epigenetic machinery and their potential use as therapeutics in MM remain to be investigated. Here, we provide evidence that the expression of de novo DNA methyltransferases (DNMTs) is deregulated in MM cells. Moreover, we show that miR-29b targets DNMT3A and DNMT3B mRNAs and reduces global DNA methylation i

Proteasome and PARP1 dual-target inhibitor for multiple myeloma: Fluzoparib.

One of the current mainstream treatments for multiple myeloma (MM) is chemotherapy. However, due to the high clonal heterogeneity and genomic complexity of MM, single-target drugs have limited efficacy and are prone to drug resistance. Therefore, there is an urgent need to develop multi-target drugs against MM. We screened drugs that simultaneously inhibit poly(ADP-ribose) polymerase 1 (PARP1) and 20S proteasome through computer-aided drug discovery (CADD) techniques, and explored the binding mode and dynamic stability of selected inhibitor to proteasome through Molecular biology (MD) simulati

Ось MLKLOPTN регулирует вызванные герпесвирусом неврологические сиквелы.

КОЛИЧЕСТВО: герпес просторексовый вирус-1 (HSV-1) носит пожизненный характер и связан с неврологическими заболеваниями, такими, как множественный склероз (MS), однако основные механизмы в хосте остаются недостаточно понятными. МЕТОДЫ И РЕЗУЛЬТАТЫ: В настоящем исследовании изучается новая молекулярная динамика после заражения HSV-1, выявляется ключевая роль смешанного киназа-домена (MLKL). Помимо известной функции в некроптозе, было установлено, что MLKL контролирует перенос HSV-1 в ядро, жестко регулируемый Оптинёрином (Optineurin). Мы продемонстрировали существенное нормативное взаимодействие

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms.

The field of transcriptional regulation has revealed the vital role of chromatin modifiers in human diseases from the beginning of functional exploration to the process of participating in many types of disease regulatory mechanisms. Chromatin modifiers are a class of enzymes that can catalyze the chemical conversion of pyrimidine residues or amino acid residues, including histone modifiers, DNA methyltransferases, and chromatin remodeling complexes. Chromatin modifiers assist in the formation of transcriptional regulatory circuits between transcription factors, enhancers, and promoters by reg

FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review.

Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug