The antitumor antibiotic mithramycin A (MTA) binds to G/C-rich DNA sequences in the presence of dications. MTA inhibits transcription regulated by the Sp1 transcription factor, often enhanced during tumor development. It shows antitumor activity, but its clinical use was discontinued due to toxic side effects. However, recent observations have led to its use being reconsidered. The MTA biosynthetic pathways have been modified to produce mithramycin analogs (mithralogs) that encompass lower toxicity and improved pharmacological activity. Some mithralogs reduce gene expression in human ovarian and prostate tumors, among other types of cancer. They down-regulate gene expression in various cellular processes, including Sp1-responsive genes that control tumor development. Moreover, MTA and several mithralogs, such as EC-8042 (DIG-MSK) and EC-8105, effectively treat Ewing sarcoma by inhibiting transcription controlled by the oncogenic EWS-FLI1 transcription factor.

Mithramycin and its analogs: Molecular features and antitumor action.

Pharmacology & Therapeutics

Hypertensive emergencies cause substantial morbidity and mortality, particularly when acute organ injury is present. Careful and effective strategies to reduce blood pressure and diminish the effects of pressure-mediated injury are essential. While the selection of specific antihypertensive medications varies little across different forms of hypertensive emergencies, the intensity of blood pressure reduction to the target pressure differs substantially. Treatment hinges on balancing the positive effects of lowering blood pressure with the potential for negative effects of organ hypoperfusion in patients with altered autoregulatory mechanisms. When patients do not have acute organ injury in addition to severe hypertension, they benefit from a conservative, outpatient approach to blood pressure management. In all cases, long term control of blood pressure is paramount to prevent recurrent hypertensive emergencies and improve overall prognosis. This review discusses the current evidence and guidelines on the evaluation and management of hypertensive emergency.

Evaluation and management of hypertensive emergency.

BMJ : British Medical Journal

Light chain deposition disease (LCDD) is a rare hematologic disorder characterized by the deposition of non-amyloid monoclonal light chains in several organs. Together with renal impairment is being the primary morbidity associated with this disease. Due to its rarity, randomized clinical trials lack to explore treatment strategies and there are no approved or universally accepted standard of care treatment options. We aimed to provide a systematic summary of histological and clinical aspects of LCDD and treatment options of available literature therapies strategies. Currently, drugs used to treat multiple myeloma are recommended when LCDD patients also presented multiple myeloma. Anyway, in patients with LCDD that is not associated to multiple myeloma, haematopoietic stem cell transplantation (ASCT) and chemotherapy with thalidomide, dexamethasone, bortezomib are also recommended. In eligible patients, bortezomib-based chemotherapy followed by ASCT appears to be an effective treatment option with durable hematologic remission and organ responses. Although it appears that the patients undergoing ASCT seem to achieve deeper and durable hematologic remissions and organ responses, no statistically significant superiority can be demonstrated over non-transplant or standard chemotherapy-based approaches. As retrieved by our review, bortezomib-based therapy appears to be favorable strategy as long as no dose modification is required for renal impairment, and early hematologic responses as a recovery of renal function. Encouraging data were also demonstrated by treatment lenalidomide or melpalan based. Moreover, new myeloma treatment strategies, as monoclonal antibody Daratumumab, seem to be effective in LCDD. Instead, renal allograft is not recommended, due to high incidence of relapse.

Light chain deposition disease: pathogenesis, clinical characteristics and treatment strategies.

Annals of Hematology

The most common four neurodegenerative atypical parkinsonian disorders (APDs) are progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). Their formal diagnostic criteria often require subspecialty experience to implement as designed and all require excluding competing diagnoses without clearly specifying how to do that. Validated diagnostic criteria are not available at all for many of the other common APDs, including normal pressure hydrocephalus (NPH), vascular parkinsonism (VP), or drug-induced parkinsonism (DIP). APDs also include conditions of structural, genetic, vascular, toxic/metabolic, infectious, and autoimmune origin. Their differential diagnosis can be challenging early in the course, if the presentation is atypical, or if a rare or non-neurodegenerative condition is present. This review equips community general neurologists to make an early provisional diagnosis before, or in place of, referral to a tertiary center. Early diagnosis would allay diagnostic uncertainty, allow prompt symptomatic management, provide disease-specific information and support resources, avoid further pointless testing and treatments, and create the possibility of trial referral.

We address 64 APDs using one over-arching flow diagram and a series of detailed tables. Most instances of APDs can be diagnosed with a careful history and neurological exam, along with a non-contrast brain MRI. Additional diagnostic tests are rarely needed but are delineated where applicable. Our diagnostic algorithm encourages referral to a tertiary center whenever the general neurologist feels it would be in the patient's best interest. Our algorithm emphasizes that the diagnosis of APDs is an iterative process, refined with the appearance of new diagnostic features, availability of new technology, and advances in scientific understanding of the disorders. Clinicians' proposals for all diagnostic tests for the APDs, including repeat visits, should be discussed with patients and their families to ensure that the potential information to be gained aligns with their larger clinical goals.

We designed this differential diagnostic algorithm for the APDs to enhance general neurologists' diagnostic skills and confidence and to help them address the less common or more ambiguous cases.

A General Neurologist's Practical Diagnostic Algorithm for Atypical Parkinsonian Disorders: A Consensus Statement.

Neurology. Clinical Practice

Immunoglobulin A nephropathy (IgAN) often has a poor outcome, with many patients reaching kidney failure within their lifetime. Therefore, the primary goal for the treatment of IgAN should be to reduce nephron loss from the moment of diagnosis. To achieve this, IgAN must be recognized and treated as both a chronic kidney disease and an immunological disease. Agents that have received US Food and Drug Administration and European Medicines Agency approval for the treatment of IgAN include modified-release/targeted-release formulation budesonide (Nefecon) and sparsentan, a selective dual endothelin-A and angiotensin II receptor type 1 antagonist. Other agents, including selective endothelin receptor antagonists, selective or combined APRIL and BAFF antagonists, and a vast array of complement inhibitors are being investigated for the treatment of IgAN. Furthermore, treatment combinations are also being studied, including sodium-glucose cotransporter-2 inhibitors with endothelin receptor antagonists. Due to the complexity of IgAN, combination treatment, rather than a single-agent approach, may provide maximum benefit. With the number of treatments for IgAN likely to increase, combinations allowing safe and effective treatment to halt progression to kidney failure seem within grasp. While trials evaluating combinations are ongoing, more are needed to pave the way for a comprehensive IgAN treatment strategy. Furthermore, an approach to IgAN treatment in which agents are combined early to achieve rapid induction of remission and prevent unnecessary and irreversible nephron loss is required. Following remission, treatments may be adjusted and stripped back as necessary in the maintenance phase with close monitoring. This review discusses the current status of IgAN treatment and explores future strategies to improve outcomes for patients with IgAN.

Therapy of IgA nephropathy: time for a paradigm change.

Frontiers in Medicine

This Recommendation was developed by the Japanese Society of Intravenous Anesthesia Recommendation Making Working Group (JSIVA-WG) to promote the safe and effective practice of total intravenous anesthesia (TIVA), tailored to the current situation in Japan. It presents a policy validated by the members of JSIVA-WG and a review committee for practical anesthesia management. Anesthesiologists should acquire and maintain the necessary knowledge and skills to be able to administer TIVA properly. A secure venous access is critically important for TIVA. To visualize and understand the pharmacokinetics of intravenous anesthetics, use of real-time pharmacokinetic simulations is strongly recommended. Syringe pumps are essential for the infusion of intravenous anesthetics, which should be prepared according to the rules of each individual anesthesia department, particularly with regard to dilution. Syringes should be clearly labeled with content and drug concentration. When&#xa0;managing TIVA, particularly with the use of muscle relaxants, monitoring processed electroencephalogram (EEG) is advisable. However, the depth of sedation/anesthesia must be assessed comprehensively using various parameters, rather than simply relying on a single EEG index. TIVA should be swiftly changed to an alternative method that includes inhalation anesthesia if necessary. Use of antagonists at emergence may be associated with re-sedation risk. Casual administration of antagonists and sending patients back to surgical wards without careful observation are not acceptable.

Recommendation for the practice of total intravenous anesthesia.

Journal of Anesthesia

Noninvasive ventilation (NIV) is the mainstay to treat patients who need augmentation of ventilation for acute and chronic forms of respiratory failure. The last several decades has witnessed an extension of the indications for NIV to a variety of acute and chronic lung diseases. Evolving advancements in technology and personalised approaches to patient care make it feasible to prioritise patient centered care models that deliver home-based management using telemonitoring and telemedicine systems support. These trends may improve patient outcomes, reduce healthcare costs, and improve the quality of life for patients who suffer from chronic diseases that precipitate respiratory failure.

Clinical Review of Non-invasive Ventilation.

European Respiratory Journal

The evaluation of the left atrial (LA) size using the LA volume index (LAVI) is clinically relevant due to its prognostic significance in various conditions. Nonetheless, adding a LA function assessment to the LAVI provides further clinical and prognostic information in different cardiovascular (CV) diseases. The assessment of LA function by echocardiography primarily includes volumetric measurements (LA ejection fraction [LAEF]), tissue Doppler imaging (TDI) (mitral annular late diastolic velocity [a']), and speckle-tracking methods, such as LA longitudinal reservoir strain (LA strain). This review analyzes and discusses the current medical evidence and potential clinical usefulness of these different methods to analyze LA function.

Current and Clinically Relevant Echocardiographic Parameters to Analyze Left Atrial Function.

Journal of Cardiovascular Development and Disease

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 8570 new patients annually and representing ~10% of all lymphomas in the United States.

HL is composed of two distinct disease entities: classical HL and nodular lymphocyte predominant HL (also called nodular lymphocyte predominant B-cell lymphoma). Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups of classical HL.

An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography (PET) scan, are used to optimize therapy.

Initial therapy for HL patients is based on the histology of the disease, the anatomical stage and the presence of poor prognostic features. Patients with early-stage disease are typically treated with combined modality strategies utilizing abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, whereas those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. However, newer agents including brentuximab vedotin and anti-PD-1 antibodies are now standardly incorporated into frontline therapy.

High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, PD-1 blockade, non-myeloablative allogeneic transplant or participation in a clinical trial should be considered.

Hodgkin lymphoma: 2025 update on diagnosis, risk-stratification, and management.

American Journal of Hematology

Guidelines help physicians to provide optimal care for stroke patients, but implementation is challenging due to the quantity of recommendations. Therefore a practical overview related to applicability of recommendations can be of assistance.

A systematic review was performed on ischaemic stroke guidelines published in scientific journals, covering the whole acute care process for patients with ischaemic stroke. After data extraction, experts rated the recommendations on dimensions of applicability, that is, actionability, feasibility and validity, on a 9-point Likert scale. Agreement was defined as a score of &#x2265;8 by &#x2265;80% of the experts.

Eighteen articles were identified and 48 recommendations were ultimately extracted. Papers were included only if they described the whole acute care process for patients with ischaemic stroke. Data extraction and analysis revealed variation in terms of both content and comprehensiveness of this description. Experts reached agreement on 34 of 48 (70.8%) recommendations in the dimension actionability, for 16 (33.3%) in feasibility and for 15 (31.3%) in validity. Agreement on all three dimensions was reached for seven (14.6%) recommendations: use of a stroke unit, exclusion of intracerebral haemorrhage as differential diagnosis, administration of intravenous thrombolysis, performance of electrocardiography/cardiac evaluation, non-invasive vascular examination, deep venous thrombosis prophylaxis and administration of statins if needed.

Substantial variation in agreement was revealed on the three dimensions of the applicability of recommendations. This overview can guide stroke physicians in improving the care process and removing barriers where implementation may be hampered by validity and feasibility.

Mithramycin and its analogs: Molecular features and antitumor action.

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