Conformational Tuning Shapes the Balance between Functional Promiscuity and Specialization in Paralogous Plasmodium Acyl-CoA Binding Proteins.

Paralogous proteins confer enhanced fitness to organisms via complex sequence-conformation codes that shape functional divergence, specialization, or promiscuity. Here, we dissect the underlying mechanism of promiscuous binding versus partial subfunctionalization in paralogues by studying structurally identical acyl-CoA binding proteins (ACBPs) from Plasmodium falciparum that serve as promising drug targets due to their high expression during the protozoan proliferative phase. Combining spectroscopic measurements, solution NMR, SPR, and simulations on two of the paralogues, A16 and A749, we show that minor sequence differences shape nearly every local and global conformational feature. A749 displays a broader and heterogeneous native ensemble, weaker thermodynamic coupling and cooperativity, enhanced fluctuations, and a larger binding pocket volume compared to A16. Site-specific tryptophan probes signal a graded reduction in the sampling of substates in the holo form, which is particularly apparent in A749. The paralogues exhibit a spectrum of binding affinities to different acyl-CoAs with A749, the more promiscuous and hence the likely ancestor, binding 1000-fold stronger to lauroyl-CoA under physiological conditions. We thus demonstrate how minor sequence changes modulate the extent of long-range interactions and dynamics, effectively contributing to the molecular evolution of contrasting functional repertoires in paralogues.

Neutrophil-Lymphocyte Ratio Predicting Case Severity in SARS-CoV-2 Infection: A Review.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious and has taken an enormous toll on the worldwide quality of life and the global economy, in addition to the lives lost due to coronavirus disease 2019 (COVID-19). Precautionary measures and timely identification of the infected cases are essential to minimize the spread of SARS-CoV-2. Infection with this virus causes a spike in the proinflammatory cytokines, resulting in immune system-mediated host tissue damage, thus leading to mortality. Therefore, identifying mild, moderate, and severe cases is crucial to rendering appropriate care. Recent research has focused on identifying laboratory techniques to predict the case severity and outcome of COVID-19 cases. Low serum lymphocyte levels, low lymphocyte-to-C-reactive protein ratio, low platelet-to-lymphocyte ratio, thrombocytopenia, and high neutrophil-lymphocyte ratio (NLR) have been observed in critical infections. NLR might be a prognostic marker for disease severity. Severe cases can be triaged at hospital admission for proper treatment planning and to reduce mortality. This review highlights the potential role of NLR hematological assay in SARS-CoV-2 infection and the mechanism of neutrophilic-induced host tissue damage.

A review of FLT3 inhibitors in acute myeloid leukemia.

FLT3 mutations are the most common genetic aberrations found in acute myeloid leukemia (AML) and associated with poor prognosis. Since the discovery of FLT3 mutations and their prognostic implications, multiple FLT3-targeted molecules have been evaluated. Midostaurin is approved in the U.S. and Europe for newly diagnosed FLT3 mutated AML in combination with standard induction and consolidation chemotherapy based on data from the RATIFY study. Gilteritinib is approved for relapsed or refractory FLT3 mutated AML as monotherapy based on the ADMIRAL study. Although significant progress has been made in the treatment of AML with FLT3-targeting, many challenges remain. Several drug resistance mechanisms have been identified, including clonal selection, stromal protection, FLT3-associated mutations, and off-target mutations. The benefit of FLT3 inhibitor maintenance therapy, either post-chemotherapy or post-transplant, remains controversial, although several studies are ongoing.

Venetoclax for the treatment of elderly or chemotherapy-ineligible patients with acute myeloid leukemia: a step in the right direction or a game changer?

INTRODUCTION: Acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis and high rates of relapse, especially in elderly patients who are ineligible to receive intensive chemotherapy. Venetoclax, an oral BCL-2 inhibitor, is approved by the Food and Drug Administration in combination with hypomethylating agents or low-dose cytarabine in newly-diagnosed AML patients who are ineligible to receive intensive chemotherapy. Confirmatory phase III VIALE-A and VIALE-C trials showed a composite complete remission rate of 66.4% and 48%, respectively. Thus, further validating venetoclax as an attractive therapeutic option in the AML treatment landscape. AREAS COVERED: A review of venetoclax in AML, focusing on preclinical and clinical data, toxicity profile, and mechanisms of resistance; and its strengths and weaknesses in regards to its current and future role in AML treatment is discussed. To find relevant studies, authors searched PubMed/Medline and ClinicalTrials.gov. EXPERT OPINION: The introduction of venetoclax-based combination therapies has greatly expanded the therapeutic options for elderly and chemotherapy-ineligible AML patients. Additional studies with extended follow-up are necessary to address remaining open questions such as (I) durability of responses, (II) head-to-head comparisons with intensive chemotherapy in selected patients (e.g. TP53 mutations), and (III) novel triplet combinations using an HMA-venetoclax backbone.

A Clinical Study of Prevalence of Microalbuminuria in Patients of Primary Hypertension and its Correlation with Left Ventricular Mass Index.

INTRODUCTION: Hypertension is one of the most challenging health problems in the world. Hypertension is closely related to kidney diseases. Microalbuminuria is a reflection of early kidney dysfunction and a marker of asymptomatic preclinical disease which precedes and predicts the occurrence of major morbid events. AIMS AND OBJECTIVES: To investigate the relationship between microalbuminuria and LVH in patients with primary hypertension. To establish microalbuminuria as an independent risk factor for increased Left Ventricular Mass Index in patients with Primary Hypertension. METHODS: This was a cross-sectional prevalence, analytical study conducted for a period of two years in a tertiary care teaching hospital in Western India. 126 patients diagnosed as primary hypertension, according to JNC 7 criteria were included in the study. Left ventricular Mass Index was measured using 2 D Echo Machine using the formula of Left ventricular mass. Multiple logistic regression was conducted to find out independent correlation of Left Ventricular Hypertrophy. RESULTS: Mean age was 64.32 years in patients without LVH while it was 63.85 years in patients with LVH. Serum creatinine, albumin-creatinine ration and Microalbuminuria were independently correlated with the Left Ventricular hyper trophy. Multiple logistic regression concluded that presence of microalbuminuria increases risk of LVH 2.04 times more as compared to absence of microalbuminuria. Serum creatinine level was higher in patients with LVH compare to patients without LVH. patients with Microalbuminuria were higher in LVH group compare to non LVH group and this difference was statistically significant. CONCLUSION: This study demonstrates that microalbuminuria has an independent correlation with Left Ventricular Mass Index and hence an independent risk factor for increased cardiovascular morbidity and mortality.

Immunohistochemical evaluation of lymphovascular invasion in carcinoma breast with CD34 and D2-40 and its correlation with other prognostic markers.

BACKGROUND: Carcinoma breast is ever-evolving and becoming increasingly prevalent in India. Numerous prognostic factors based on morphology and immunohistochemistry (IHC) have been established which need to be interconnected to give patients best possible treatment. AIMS: This study aims to confirm and analyze lymphovascular invasion (LVI) detected by hematoxylin and eosin (H and E) using IHC with CD34 and D2-40 and its correlation with other biologic and morphologic prognostic markers. SETTINGS AND DESIGN: This was a prospective study. MATERIALS AND METHODS: Fifty mastectomy specimens diagnosed as infiltrating ductal carcinoma breast on histopathology selected for the study. Evaluation of formalin-fixed paraffin-embedded sections was done using H and E and IHC for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 HER2/neu receptors, CD34, and D2-40 endothelial markers. Correlation of LVI done with prognostic markers of Carcinoma Breast, namely, age of the patient, tumor size, Nottingham grade, lymph node ratio (LNR), Nottingham prognostic index (NPI), ER/PR status, and HER2/neu status. CD34 and D2-40 utilized to distinguish blood vessel, lymph vessel, and retraction artifacts and to calculate lymphatic microvessel density (LMVD) and blood microvessel density (BMVD). STATISTICAL ANALYSIS USED: SPSS Software Package. RESULTS: LVI was associated with younger age (P = 0.001), greater tumor size (P = 0.007), higher Nottingham grade (P = 0.001), higher LNR (P = 0.001), higher NPI (P = 0.001), Negative ER Status (P = 0.001), Negative PR Status (P = 0.002), Positive HER2/neu status (P = 0.021), Higher Intratumoral BMVD (P = 0.016), Peritumoral BMVD (P = 0.001), and Intratumoral LMVD (P = 0.009). Blood vessels more commonly invaded than lymph vessels. Retraction artifacts can be mistaken for LVI without IHC. CONCLUSIONS: D2-40 is a promising marker for lymphatic endothelium. LVI is a poor prognostic marker hence should be evaluated imperatively in all cases of carcinoma breast.

Fungal colonization in patients with chronic respiratory diseases from Himalayan region of India.

BACKGROUND: We screened patients with chronic respiratory diseases for microbiological and serological evidences of fungal colonisation; in order to determine its prevalence in this group of patients, examine potential clinical and radiological predictors of fungal colonisation and characterise fungal agents associated with individual diseases. METHODS: BAL samples from 60 consecutive patients were subjected to microscopy and culture for fungal agents. Serum samples were analysed for precipitin antibodies to Aspergillus antigen and Candida cytoplasmic antigen. Statistical significance in the difference of fungal recovery between patient groups was determined using the Chi-square test. RESULTS: The major diagnostic groups included patients with bronchogenic carcinoma (n = 31) and tubercular sequelae (n = 16). In all, 28 patients (46.7%) were culture-positive, with Candida and Aspergillus being recovered from 14 and 13 patients respectively. Twenty-one patients (35%) showed presence of precipitin antibodies. Patients with bronchogenic carcinoma showed increased predilection for colonisation with Aspergillus, while Candida was recovered more commonly in tubercular sequelae (p = 0.02). There was no statistically significant association between culture-positivity and specific risk factors/radiological findings. CONCLUSION: The point-prevalence of fungal colonization was almost 50%. The combination of fungal culture and serology helped improve diagnostic sensitivity. An interesting predilection was observed for Aspergillus and Candida, to preferentially infect patients with Bronchogenic carcinoma and Tubercular sequelae respectively. In absence of specific predictors, the possibility of fungal colonization needs to be explored actively in these patients.