Utility of KIT Mutations in Myeloid Neoplasms Without Documented Systemic Mastocytosis to Detect Hidden Mast Cells in Bone Marrow.

BACKGROUND: KIT p.D816 mutation is strongly associated with systemic mastocytosis (SM). Next-generation sequencing (NGS) is now routinely performed in almost all bone marrow sample and KIT mutations are detected from patients who are not known or suspected to have SM. Therefore, we wanted to assess if KIT mutations in this patient population are associated with unsuspected SM. METHODS: We searched NGS result in our institution with positive result for KIT mutation from patients with known/suspected myeloid neoplasms. Patients with previously documented history of systemic mastocytosis were excluded. Bone marrow biopsies from patients with KIT mutation were assessed with immunohistochemical stains for CD117 and mast cell tryptase (MST). RESULTS: Bone marrow biopsies were assessed with immunohistochemical stains for CD117 and mast cell tryptase (n = 49). Most patients had acute myeloid leukemia (AML, n = 38) or chronic myelomonocytic leukemia (CMML, n = 6). Immunohistochemical stains for CD117 and tryptase were performed in all 49 patients. A total of 4 patients (8.2%) showed mast cell nodules where spindled shaped mast cells were present, meeting the WHO criteria for SM. All four patients had KIT p.D816V mutation and had high mutant allelic frequency (∼ 50%) except one patient (1%). CONCLUSION: We discovered approximately 8% of patients who had myeloid neoplasms with unexpected KIT mutations fulfilled the diagnostic criteria for systemic mastocytosis after additional immunohistochemical studies. Our data support that application of additional immunohistochemical studies is recommended to identify underrecognized SM when KIT mutations are found by molecular assays.

Serum iron, zinc and copper among Indian patients with leukoplakia, oral submucous fibrosis and oral squamous cell carcinoma.

The serum levels of iron, zinc and copper in patients with leukoplakia, oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC) and compare them with normal subjects is of interest to dentists. The effort was to determine a parameter that will aid the initial diagnosis, a more efficient therapy plan, and ultimately a better prognosis. Participants in the study comprised 40 healthy normal volunteers, 60 patients diagnosed with leukoplakia, 60 patients diagnosed with OSCC, and 60 patients diagnosed with OSMF. After fasting for the whole night, blood samples were taken from each participant. There was analysis by inductively coupled plasma-optical emission spectrometry (ICP-OES) for the determination of trace elements; iron, copper, and zinc. The serum levels of iron and zinc in normal subjects was greater as compared to patients with leukoplakia, OSMF and OSCC. There was increase in serum copper levels in patients with oral leukoplakia, OSMF and OSCC as compared with normal subjects.

Molecular Docking of Intrinsically Disordered Proteins: Challenges and Strategies.

Intrinsically disordered proteins (IDPs) are a novel class of proteins that have established a significant importance and attention within a very short period of time. These proteins are essentially characterized by their inherent structural disorder, encoded mainly by their amino acid sequences. The profound abundance of IDPs and intrinsically disordered regions (IDRs) in the biological world delineates their deep-rooted functionality. IDPs and IDRs convey such extensive functionality through their unique dynamic nature, which enables them to carry out huge number of multifaceted biomolecular interactions and make them "interaction hub" of the cellular systems. Additionally, with such widespread functions, their misfunctioning is also intimately associated with multiple diseases. Thus, understanding the dynamic heterogeneity of various IDPs along with their interactions with respective binding partners is an important field with immense potentials in biomolecular research. In this context, molecular docking-based computational approaches have proven to be remarkable in case of ordered proteins. Molecular docking methods essentially model the biomolecular interactions in both structural and energetic terms and use this information to characterize the putative interactions between the two participant molecules. However, direct applications of the conventional docking methods to study IDPs are largely limited by their structural heterogeneity and demands for unique IDP-centric strategies. Thus, in this chapter, we have presented an overview of current methodologies for successful docking operations involving IDPs and IDRs. These specialized methods majorly include the ensemble-based and fragment-based approaches with their own benefits and limitations. More recently, artificial intelligence and machine learning-assisted approaches are also used to significantly reduce the complexity and computational burden associated with various docking applications. Thus, this chapter aims to provide a comprehensive summary of major challenges and recent advancements of molecular docking approaches in the IDP field for their better utilization and greater applicability.Asp (D).

Hematological profile of OSMF patients with increasing severity.

Haematological profile of patients with oral sub mucous fibrosis (OSMF) and its correlation with the severity of OSMF is evaluated. The study comprised of sixty participants with clinical diagnoses. They were divided into smaller groups based on the OSMF stage. Sixty age and gender matched healthy controls were chosen among patients presenting for routine hematological examinations and free of systemic illnesses. Assessment of iron, hemoglobin, and red cell indices in all study participants was carried out. It was observed that the values of haematological tests like (Hb (g/dL), PCV, MCV (fl), MCH, MCHC, Iron (mg/dL) and Vitamin B12 (pg/Ml) was greater in normal subjects as compared to OSMF patients. Values were found to decrease further as the severity (staging) of OSMF increased among OSMF patients. The findings were statistically significant showing decrease in the values of different haematological parameters as the stage of OSMF progressed from stage I to stage III.

Circadian clock neurons use activity-regulated gene expression for structural plasticity.

Drosophila s-LNv circadian pacemaker neurons show dramatic structural plasticity, with their projections expanded at dawn and then retracted by dusk. This predictable plasticity makes s-LNvs ideal to study molecular mechanisms of plasticity. Although s-LNv plasticity is controlled by their molecular clock, changing s-LNv excitability also regulates plasticity. Here, we tested the idea that s-LNvs use activity-regulated genes to control plasticity. We found that inducing expression of either of the activity-regulated transcription factors Hr38 or Sr (orthologs of mammalian Nr4a1 and Egr1) is sufficient to rapidly expand s-LNv projections. Conversely, transiently knocking down expression of either Hr38 or sr blocks expansion of s-LNv projections at dawn. We show that Hr38 rapidly induces transcription of sif, which encodes a Rac1 GEF required for s-LNv plasticity rhythms. We conclude that the s-LNv molecular clock controls s-LNv excitability, which couples to an activity-regulated gene expression program to control s-LNv plasticity.

The Efficacy of Buprenorphine in Preoperative and Postoperative Patients: A Literature Review.

Although research suggests that less than half of individuals who have surgical procedures report effective postoperative pain alleviation, the majority of patients endure acute postoperative discomfort. To lessen and manage postoperative pain, a variety of preoperative, intraoperative, and postoperative treatments and management methods are available. For several years an opioid called buprenorphine has become an effective tool to treat opioid use disorder (OUD) in patients across many different demographics. It has however endured barriers to its usage which can be seen when treating patients with chronic pain or postoperative pain, who also have an OUD. While buprenorphine may be underutilized within the clinical setting, the significantly low rates of chronic abuse when using the drug allow it to be an attractive treatment option for patients. This paper aims to explore a wide range of studies that examine buprenorphine as an analgesic and how it can be used for preoperative pain and postoperative pain. This paper will give an in-depth analysis of buprenorphine and its use in patients with chronic pain as well as OUD. A systematic literature review was performed by identifying studies through the database PubMed. The data from various publications were gathered with preference being given to publications within the last three years. We reviewed studies that examined the pain level of the patients after having buprenorphine. Despite long-available pharmacologic evidence and clinical research, buprenorphine has maintained a mystique as an analgesic. Its usage in the treatment of OUD was further influenced by its well-known safety benefits and relative lack of psychomimetic side effects compared to other opioids. For patients accustomed to long-term, high-dose opioids who may be experiencing hyperalgesia but have not been informed about this phenomenon by their doctors or the potential for buprenorphine to resolve it, buprenorphine's pronounced antihyperalgesic effect is a compelling pharmacologic characteristic that makes it particularly attractive as an option. When used in pre-, peri-, and postoperative circumstances, buprenorphine provides various pain-management benefits and patients can still benefit from effective pain management from mu-opioid agonists while remaining on buprenorphine. Buprenorphine can be continued at a reduced dose as needed to avoid withdrawal symptoms and to improve the analgesic efficiency of mu-opioid agonists used in combination with acute postoperative pain in light of the evidence at hand. Buprenorphine administration needs a patient-centered, multidisciplinary strategy that considers the benefits and drawbacks of the many perioperative therapy options to have the best chance of success.

Outcomes and genetic dynamics of acute myeloid leukemia at first relapse.

Patients with relapsed acute myeloid leukemia (rAML) experience dismal outcomes. We performed a comprehensive analysis of patients with rAML to determine the genetic dynamics and survival predictive factors. We analyzed 875 patients with newly diagnosed AML who received intensive treatment (IT) or low-intensity treatment (LIT). Of these patients, 197 experienced subsequent rAML. Data was available for 164 patients, with a median time from CR/CRi to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation (alloSCT). At relapse mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated with IT had a higher emergence rate of TP53 mutations (16%), compared to patients treated with LIT (1%, P = 0.009). The overall response rates were 38% and 35% for patients treated with salvage IT or LIT, respectively. Seventeen patients (10%) underwent alloSCT after salvage therapy. The median overall survival (OS) duration after relapse was 5.3 months, with a 1-year OS rate of 17.6%. Complex karyotype (hazard ratio [HR] = 2.14, P < 0.001), a KMT2A rearrangement (HR = 3.52, P = 0.011), time in remission < 12 months (HR = 1.71, P = 0.011), and an elevated white blood cell count at relapse (HR = 2.38, P = 0.005) were independent risk factors for OS duration. More effective frontline and maintenance therapies are warranted to prevent rAML.

Long-term results of the sequential combination of cladribine and rituximab in Hairy cell leukemia.

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40-18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings.

Unlocking Therapeutic Potential: The Role of Theta Burst Stimulation in Multiple Sclerosis Management.

Objective: Current therapies for multiple sclerosis (MS) often have limited efficacy and side effects, necessitating alternative approaches. Noninvasive brain stimulation (NIBS), such as transcranial direct current stimulation and transcranial magnetic stimulation (TMS), offers potential solutions. Among NIBS techniques, theta burst stimulation (TBS) is notable for its ability to modulate cortical activity. The objective of this systematic review is to assess the impact of TBS on MS symptoms.Data Sources: The study conducted rigorous systematic searches in PubMed, Google Scholar, and Scopus databases up to June 2023, using specific Medical Subject Headings terms related to NIBS and MS, such as TMS and TBS, in conjunction with terms like MS or demyelinating disease. Additionally, the bibliographic references of included studies, book chapters, and original articles were manually reviewed.Study Selection: The study selection process involved a 2-tiered screening mechanism, beginning with an evaluation of titles and abstracts, followed by a full-text review of selected articles. Inclusion criteria incorporated randomized controlled trials (RCTs) focusing on TBS with MS patients. Exclusion criteria included non-qualitative, non-MS, and non-TBS studies. Risk of bias assessment was conducted using the 2008 Cochrane Risk of Bias 2 Scale for RCTs.Data Extraction: Data extraction was conducted by thoroughly reviewing each research article and systematically recording the relevant information using a standardized data extraction form, ensuring consistency and accuracy throughout the process.Results: In a systematic review encompassing 5 randomized controlled trials involving 117 individuals with relapsing-remitting or secondary progressive MS across Italy, France, and Russia, various forms of TBS were applied. These interventions ranged from intermittent TBS (iTBS) to continuous intermittent TBS (c-iTBS) that demonstrated favorable outcomes. Notably, TBS interventions led to significant reductions in spasticity, fatigue, and pain, with c-iTBS combined with vestibular rehabilitation showing additional improvements in vestibular-ocular reflexes, gait, and balance. While specific protocols varied among the studies, collectively, the results suggest promise for TBS approaches in alleviating MS-related symptoms.Conclusions: The findings of this review suggest that TBS may hold promise in addressing specific MS symptoms, notably fatigue and spasticity. Future research should include a more diverse participant pool to explore TBS effects across different MS subtypes and aim for larger sample sizes to enhance statistical power and result reliability.Prim Care Companion CNS Disord 2024;26(2):23r03645. Author affiliations are listed at the end of this article.

Childhood and Adolescent Relapsed/Refractory Aggressive B-Cell Lymphomas With t(8;14) and BCL2 Expression, Burkitt Lymphoma Versus Diffuse Large B-Cell Lymphoma: A Diagnostic Challenge.

We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as "DLBCL-NOS with MYC rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA).

Noninvasive liver disease assessment to identify portal hypertension: Systematic and narrative reviews supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Portal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. HVPG, a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and availability, noninvasive liver disease assessments to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed. APPROACH AND RESULTS: We conducted a systematic review of Ovid MEDLINE(R) Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database's inception to April 22, 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies, which compared noninvasive tests (blood and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥ 10 mm Hg) in patients with chronic liver disease. Outcomes included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided. Nine studies with 2492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood-based tests, including aspartate-to-platelet ratio index (APRI) (56% sensitivity and 68% specificity) and FIB-4 (54% sensitivity and 73% specificity) had low accuracy measures. Imaging-based tests (transient elastography and shear wave elastography detection of liver stiffness measurement [LSM]) had better accuracy but also had substantial variation; at 15 kPa, TE sensitivity was 90%-96% and specificity was 48%-50%, while at 25 kPa, its sensitivity and specificity were 57%-85% and 82%-93%, respectively. The narrative review suggested that imaging-based tests are the best available noninvasive liver disease assessment to detect CSPH; CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa. CONCLUSIONS: While imaging-based noninvasive liver disease assessment appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the systematic review. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.

Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Blood-based biomarkers have been proposed as an alternative to liver biopsy for noninvasive liver disease assessment in chronic liver disease. Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4), as compared to biopsy in chronic liver disease. APPROACH AND RESULTS: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in HBV and HCV, HIV-HCV/HBV coinfection, and NAFLD. Positive (LR+) and negative (LR-) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66-6.25 and 0.23-0.80, 1.89-5.24 and 0.12-0.64, and 1.32-7.15 and 0.15-0.86, respectively; LR+ and LR- for NAFLD F2-4, F3-4, and F4 were 2.65-3.37 and 0.37-0.39, 2.25-6.76 and 0.07-0.87, and 3.90 and 0.15, respectively. Overall, the proportional odds ratio indicated FIB-4 <1.45 was better than aspartate aminotransferase-to-platelet ratio index <0.5 for F2-4. FIB-4 >3.25 was also better than aspartate aminotransferase-to-platelet ratio index >1.5 for F3-4 and F4. There was limited data for combined tests. CONCLUSIONS: Blood-based biomarkers are associated with small-to-moderate change in pretest probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV coinfection, and NAFLD, with limited comparative or combination studies for other chronic liver diseases.

Noninvasive assessment of liver fibrosis and portal hypertension.

PURPOSE OF REVIEW: The result of ongoing liver injury - and disease, regardless of cause - is fibrosis, and fibrosis appears to be a critically important result of ongoing injury. Further, in a number of different liver diseases, the presence of fibrosis has prognostic value. Therefore, the assessment of fibrosis is of critical clinical importance. Given the importance of fibrosis, there has been a rapid evolution in the use of noninvasive liver tests. This review highlights a number of the core principles surrounding. RECENT FINDINGS: The use of noninvasive test has progressed rapidly over the last decade and data are rapidly accumulating. New terminology has been adapted by the American Association for the Study of Liver Disease (AASLD) for noninvasive assessment of liver disease and termed 'NILDA' (Non-Invasive Liver Disease Assessment). Blood based such as APRI and or FIB-4 and imaging tests such as liver stiffness measurement (LSM) have moderate to high degrees of accuracy for detection of advanced liver fibrosis (≥ F2) and even higher accuracy for detection of severe fibrosis (F4 or cirrhosis). NILDA are particularly effective at the ends of the liver disease spectrum. For example, a very low LSM (less than 7 kPa) essentially excludes significant fibrosis or portal hypertension, and a very high LSM (> 25 kPa) makes significant fibrosis with portal hypertension (cirrhosis) highly likely. SUMMARY: NILDA are currently front and center in terms of assessment of the severity of liver disease. In all patients with known or suspected liver disease, noninvasive blood tests, including APRI and or FIB-4, should be the initial choice to assess the severity of liver fibrosis and/or portal hypertension. In most patients, these tests should be followed with imaging evaluation. The most commonly available imaging is LSM, which appears to be more accurate in predicting fibrosis severity, and is superior to blood tests in the assessment of portal hypertension. In situations in which there is diagnostic uncertainly, liver biopsy with or without HVPG remains an important consideration.