Alternative Treatment Regimens Research Articles

Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length

BackgroundLarge B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.ResultsWe studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499–31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286–18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239–21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319–27.397) and PFS (HR 4.689, 95% CI 1.102–19.963) in LBCL treated with R-CHOP-like regimens.ConclusionWe hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.

Exploring rhodanine linked enamine-carbohydrazide derivatives as mycobacterial carbonic anhydrase inhibitors: Design, synthesis, biological evaluation, and molecular docking studies.

With the rise of multidrug-resistant tuberculosis, the imperative for an alternative and superior treatment regimen, incorporating novel mechanisms of action, has become crucial. In pursuit of this goal, we have developed and synthesized a new series of rhodanine-linked enamine-carbohydrazide derivatives, exploring their potential as inhibitors of mycobacterial carbonic anhydrase. The findings reveal their efficacy, displaying notable selectivity toward the mycobacterial carbonic anhydrase 2 (mtCA 2) enzyme. While exhibiting moderate activity against human carbonic anhydrase isoforms, this series demonstrates promising selectivity, positioning these compounds as potential antitubercular agents. Compound 6d was the best one from the series with a Ki value of 9.5 µM toward mtCA 2. Most of the compounds displayed moderate to good inhibition against the Mtb H37Rv strain; compound 11k showed a minimum inhibitory concentration of 1 µg/mL. Molecular docking studies revealed that compounds 6d and 11k show metal coordination with the zinc ion, like classical CA inhibitors.

Real-World Clinical Performance of a DNA-Based Comprehensive Genomic Profiling Assay for Detecting Targetable Fusions in Nonsquamous NSCLC.

Genomic fusions are potent oncogenic drivers across cancer types and many are targetable. We demonstrate the clinical performance of DNA-based comprehensive genomic profiling (CGP) for detecting targetable fusions. We analyzed targetable fusion genes in >450000 tissue specimens profiled using DNA CGP (FoundationOne CDx, FoundationOne). Using a de-identified nationwide (US-based) non-small cell lung cancer (NSCLC) clinico-genomic database, we assessed outcomes in patients with nonsquamous NSCLC (NonSqNSCLC) who received matched therapy based on a fusion identified using DNA CGP. Lastly, we modeled the added value of RNA CGP for fusion detection in NonSqNSCLC. We observed a broad diversity of fusion partners detected with DNA CGP in conjunction with targetable fusion genes (ALK, BRAF, FGFR2, FGFR3, NTRK1/2/3, RET, and ROS1). In NonSqNSCLC with oncogenic ALK, NTRK, RET, and ROS1 fusions detected by DNA CGP, patients treated with a matched tyrosine kinase inhibitor had better real-world progression-free survival than those receiving alternative treatment regimens and benefit was observed regardless of the results of orthogonal fusion testing. An estimated 1.3% of patients with NonSqNSCLC were predicted to have an oncogenic driver fusion identified by RNA, but not DNA CGP, according to a model that accounts for multiple real-world factors. A well-designed DNA CGP assay is capable of robust fusion detection and these fusion calls are reliable for informing clinical decision-making. While DNA CGP detects most driver fusions, the clinical impact of fusion detection is substantial for individual patients and exhaustive efforts, inclusive of additional RNA-based testing, should be considered when an oncogenic driver is not clearly identified.

Treatment Response to Neoadjuvant Therapy in Squamous Esophageal Cancer-Correlation Between Metabolic Response and Histopathology.

Esophageal cancer is among the leading causes of cancer-related mortality worldwide. Patients presenting with localized and loco-regionally advanced cancer without distant metastases have reasonable survival with multimodality management. Adequate and comprehensive staging is the backbone for proper selection of patients fit for curative treatment. Positron emission tomography (PET) in combination with contrast-enhanced computed tomography (CECT) is utilized as the standard staging modality. Multimodality treatment has been able to achieve evaluable tumor responses including pathological complete response (pCR). It is, therefore, necessary to understand whether the impact of neoadjuvant therapy can be evaluated on imaging, i.e., standardized uptake value (SUV) on PET scan done for response assessment and if this can be correlated with histopathological response and later, with survival. Squamous cell carcinoma (SCC) is more common globally and in the Indian subcontinent; hence, we chose this subgroup to evaluate our hypothesis. This is a single institution, retrospective study. Out of the 1967 patients who were treated between 2009 and 2019, 1369 (78.54%) patients had SCC. Out of these, 44 received NACTRT, whereas 1325 received NACT followed by curative surgery. The standardized uptake value (SUV) of 18-fluorodeoxyglucose was recorded during pre- and post-neoadjuvant treatment (NAT) using positron emission tomography (PET). The histopathology of the final resection specimen was evaluated using the Mandard tumor regression grade (TRG) criteria with response being graded from 0 to 5 as no residual tumor (NRT), scanty residual tumor (SRT), and residual tumor We attempted to find a cut-off value of the post neoadjuvant SUV of the primary tumor site which correlated with achievement of better histopathological response. Out of 1325 patients of SCC esophagus who underwent surgery, 943 patients had available data of TRG, and it was categorized into the 0-2 category which had 325 patients (34.5%) and 3-5 category, 618 patients (65.5%). The SUV was taken only from the PET scans done at our institution, so as to achieve a more homogenous cohort, and this was available for 186 patients, 151 from the NACT group and 35 from the NACTRT group. The ROC method was used to find the cut-off for SUV (5.05) in the NACT cohort, which depicted significant difference in the outcome. Out of these, 93 patients who underwent NACT had SUV > 5.05 and 58 had SUV < 5.05. It was found that the subjective and objective histopathological scores correlated at a p value of < 0.0001. Specifically, the majority of cases with SRT tended to be in the 3-5 category of TRG, whereas cases with NRT are predominantly in the 0-2 category. In the ≥ 5.05 category of SUV, there were 76 cases with SRT. In the NACT cohort, the < 5.05 category of SUV, there are 26 cases with SRT and 32 cases with NRT. Among cases with SRT, 74.5% had SUV ≥ 5.05, while 25.5% had SUV < 5.05. Among cases with NRT, 34.7% had SUV ≥ 5.05, while 65.3% had SUV < 5.05 (p value 0.007). No significant association was found in the radio-pathological correlation in the NACTRT group. Our study confirms the correlation of post neoadjuvant chemotherapy PET SUV with histopathological response, the cut-off of SUV being 5.05 in our cohort. This confirms the predictive value of FDG PET as demonstrated in other studies. Furthermore, its prognostic value with respect to survival has been verified in multiple other studies. With larger scale randomized studies, we may be able to identify the group of patients who have borderline operability anatomically as well as physiologically, where alternative treatment regimens may be indicated to improve outcomes.

Peranan Sekuen Diffusion Weighted Imaging (DWI) Pada Pemeriksaan MRI Soft Tissue Leher Kasus Kanker Nasofaring (Studi Literatur)

The aim of this research is to determine the role of the Diffusion Weighted Imaging (DWI) sequence in Soft Tissue MRI examinations of the neck in cases of nasopharyngeal cancer and to determine the advantages of using the Diffusion Weighted Imaging (DWI) sequence in MRI Soft Tissue examinations of the neck in cases of nasopharyngeal cancer. The research method used was a descriptive qualitative research method with a literature study method. The results of the literature review research showed: 1) Nasopharyngeal cancer, especially squamous cell carcinoma, can be treated with radiation therapy where treatment failure is still a serious problem, especially in advanced cases. DWI and ADC are imaging methods that utilize the movement of water inside. DWI provides additional information regarding response to treatment in hard-to-reach cases of nasopharyngeal cancer. plays an important role in detection, evaluation of response to treatment, and early monitoring of chemoradiotherapy therapy. DWI also provides information that helps distinguish between tissue experiencing post-RTH fibrosis and areas that may contain active cancer cells. DWI and ADC are also useful in tumor staging, delineation of target volumes, and detection of tumor recurrence. Elevated ADC may be indicative of a favorable response to therapy, whereas low pretreatment ADC values ​​may predict a favorable response. In the diagnosis of nasopharyngeal cancer, DWI and ADC also help differentiate squamous cell carcinoma subtypes, predict response to chemoradiation therapy, and determine the appropriate time for alternative treatment regimens. 2) DWI and ADC provide advantages in the diagnosis and monitoring of nasopharyngeal cancer. DWI can image restrictions on water diffusion within tissue, helping to detect areas of high cell density associated with tumors. Its advantages include sensitivity to microenvironmental changes and the ability to early identify recurrence or secondary cancer post-radiation therapy.

Management of acute coronary syndrome : ESC guidelines 2023

The new guidelines of the European Society of Cardiology (ESC) on the management of acute coronary syndrome (ACS) in 2023 encompass updates for both the guidelines pertaining to ST elevation myocardial infarction (STEMI) and acute coronary syndrome without ST segment elevation (NSTE-ACS). The previously separated guidelines from 2017 and 2020 were therefore revised and summarized. These guidelines address various topics, including diagnostics, acute management, antithrombotic treatment, out-of-hospital cardiac arrest, cardiogenic shock, invasive strategies, and long-term treatment. The notable updates compared to earlier guidelines address the recommendation regarding the timing of invasive diagnostics in NSTE-ACS (Non-ST elevation acute coronary syndrome), the procedure of revascularization in multivessel coronary artery disease and alternative regimens for antithrombotic treatment in patients with a high risk of bleeding.

Antibiotic prescription patterns in Spanish cystic fibrosis patients: results from a national multicenter study

ObjectiveInformation about antibiotic prescription patterns for cystic fibrosis (CF) patients and, specifically, about inhaled treatment strategies for their management is lacking in Spain due to the absence of a national patient registry. In this study we present data about antibiotic prescription in the Spanish CF context that were obtained in a multicenter study, being inhaled treatment strategies the special focus of this work. MethodsTwenty-four specialized CF units (12 adult, 12 pediatric) from 17 tertiary-care hospitals covering all Spanish Autonomous Communities provided sputa and clinical data from 15 consecutive patients. Data about antibiotic and non-antibiotic therapies prescribed to these patients during the year prior inclusion (2013) were retrospectively collected. ResultsThe multicenter study included 341 CF patients from all age groups and clinical status. The prevalence of oral, inhaled and intravenous therapies was 89% (n = 302), 80% (n = 273) and 31% (n = 105), respectively. The most prevalent oral agents were ciprofloxacin (n = 177, 59%), cotrimoxazole (n = 109, 36%) and amoxicillin-clavulanate (n = 99, 33%), whereas ceftazidime (n = 53, 50%), tobramycin (n = 43, 41%) and meropenem (n = 41, 49%) were the most prevalent intravenous ones. Two or more different inhaled antibiotics were administered to 67 patients (24%), 51 of them receiving 2 drugs continuously in alternating schemes. Nebulization of intravenous specific antibiotics was common (n = 39) and, in some cases, was used for maintenance purposes. ConclusionsThese results show that the treatment of CF patients is evolving more rapidly than clinical consensus guidelines. Clinical trials evaluating new specific inhaled combinations and new alternative treatment regimes of the existing ones are needed.

Strategies to combat Gram-negative bacterial resistance to conventional antibacterial drugs: a review.

The emergence of antimicrobial resistance raises the fear of untreatable diseases. Antimicrobial resistance is a multifaceted and dynamic phenomenon that is the cumulative result of different factors. While Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus and Clostridium difficile, were previously the most concerning issues in the field of public health, Gram-negative pathogens are now of prime importance. The World Health Organization's priority list of pathogens mostly includes multidrug-resistant Gram-negative organisms particularly carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and extensively drug-resistant Acinetobacter baumannii. The spread of Gram-negative bacterial resistance is a global issue, involving a variety of mechanisms. Several strategies have been proposed to control resistant Gram-negative bacteria, such as the development of antimicrobial auxiliary agents and research into chemical compounds with new modes of action. Another emerging trend is the development of naturally derived antibacterial compounds that aim for targets novel areas, including engineered bacteriophages, probiotics, metal-based antibacterial agents, odilorhabdins, quorum sensing inhibitors, and microbiome-modifying agents. This review focuses on the current status of alternative treatment regimens against multidrug-resistant Gram-negative bacteria, aiming to provide a snapshot of the situation and some information on the broader context.

Therapeutic Effects of Oral Application of Menthol and Extracts from Tormentil (Potentilla erecta), Raspberry Leaves (Rubus idaeus), and Loosestrife (Lythrum salicaria) during Acute Murine Campylobacteriosis.

Human food-borne infections with the enteropathogen Campylobacter jejuni are becoming increasingly prevalent worldwide. Since antibiotics are usually not indicated in campylobacteriosis, alternative treatment regimens are important. We here investigated potential disease-alleviating effects of menthol and of extracts from tormentil, raspberry leaves, and loosestrife in acute murine campylobacteriosis. Therefore, C. jejuni-infected microbiota-depleted IL-10-/- mice were orally treated with the compounds alone or all in combination from day 2 until day 6 post-infection. Whereas neither treatment regimen affected gastrointestinal pathogen loads, the combination of compounds alleviated C. jejuni-induced diarrheal symptoms in diseased mice on day 6 post-infection. Furthermore, the therapeutic application of tormentil and menthol alone and the combination of the four compounds resulted in lower colonic T cell numbers in infected mice when compared to placebo counterparts. Notably, pro-inflammatory cytokines measured in mesenteric lymph nodes taken from C. jejuni-infected mice following tormentil, menthol, and combination treatment did not differ from basal concentrations. However, neither treatment regimen could dampen extra-intestinal immune responses, including systemic pro-inflammatory cytokine secretion on day 6 post-infection. In conclusion, the combination of menthol and of extracts from tormentil, raspberry leaves, and loosestrife constitutes an antibiotic-independent approach to alleviate campylobacteriosis symptoms.

Renal dysfunction in individuals with ovarian cancer; a review on current concepts

Renal impairment is a common complication in patients with ovarian cancer. Renal impairment in ovarian cancer patients can be caused by various factors. Many of the chemotherapeutic agents administered to treat ovarian cancer are nephrotoxic and can promote kidney dysfunction, leading to renal impairment. Ovarian tumors can obstruct the urinary tract, leading to a reduction in renal function and dilation of the upper urinary tract. Acute kidney injury (AKI) can occur in ovarian cancer patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Women treated for epithelial ovarian cancer suffer an accelerated rate of renal function decline, independent of major risk factors for kidney disease. Conversely, renal impairment can affect the dosage of chemotherapy drugs used in ovarian cancer treatment. Dose reduction, dose adjustment based on pharmacokinetic data, alternative treatment regimens, and individualized dosing may be necessary to ensure optimal therapeutic outcomes while minimizing the risk of toxicity and treatment-related complications.

Retrospective Evaluation of Patients with Brucellosis: Five Years of Experience

Objective: We aimed to evaluate the epidemiological, clinical features, laboratory findings, and treatment regimens of patients with brucellosis in the Tokat region. Methods: In this cross-sectional study, the data of 236 adult patients followed with brucellosis in Tokat Gaziosmanpaşa University Medical Faculty Hospital between January 2016 and December 2021 were evaluated retrospectively. Diagnostic criteria of brucellosis were determined as culture positivity, or positivity in the Wright test at ≥ 1/160 titration, or a 4-fold increase in titer of the Wright test repeated at 2 – 3 week intervals. Demographic data, symptoms, physical examination findings, and laboratory results of the patients were evaluated. Results: 72% (n=170) of the patients were male, and the mean age was 44.47±16.64. 53% (n=125) were engaged in animal husbandry, 21.6% (n=51) consumed unpasteurized dairy products, and 13.1% (n=31) had a family member with brucellosis. Seven (2.9%) patients with a prediagnosis of Crimean-Congo hemorrhagic fever (CCHF) were diagnosed with acute brucellosis. The most common symptoms were muscle-joint pain (70.3%), fever (50.8%), and sweating (43.2%). Spondylodiscitis was observed in 13.6%, epididymal-orchitis in 8.2%, and neurobrucellosis in 0.4% of the patients. Blood culture positivity was detected in 7.2% of the cases. 91.5% had elevated C-reactive protein (CRP) levels, and 48.3% had elevated erythrocyte sedimentation rates. The most common hematological findings were anemia (28%), leukopenia (10.6%), and thrombocytopenia (8.5%). As a therapy doxycycline + rifampicin combination was started at 36%, doxycycline + gentamicin to 5.8%, doxycycline + streptomycin to 5.4%, and doxycycline + rifampicin + gentamicin to 29.7% of the patients. Alternative treatment regimens were given to 22.9% (n=54) of the patients. Conclusion: Brucellosis is still a critical zoonotic disease in our region. It should be kept in mind when diagnosing patients with fever, muscle-joint pain, and sweating, with epidemiological histories, have elevated acute phase reactants and cytopenia. It should also be remembered that brucellosis can be confused with CCHF in endemic areas.

Efficacy of anti-tuberculosis drugs for the treatment of latent tuberculosis infection: a systematic review and network meta-analysis

Despite the availability of three network meta-analyses (NMA) examining the efficacy, treatment completion, and adverse events associated with all latent tuberculosis infection (LTBI) treatments, there is currently no evidence to support the notion that the benefits of these treatments outweigh the potential risks. This NMA aimed to conduct a comprehensive comparison and update of the efficacy, treatment completion rates and adverse events associated with recommended treatment options for LTBI for individuals with confirmed LTBI, as outlined in the 2020 World Health Organization (WHO) Consolidated Guidelines for TB preventive treatment. A comprehensive search of the MEDLINE and Scopus databases was conducted until April 2023. The NMA was applied to estimate the risk difference and corresponding 95% confidence interval (CI) using a combination of direct and indirect evidence. The risk–benefit assessment was employed to evaluate the feasibility of the extra benefits in relation to the extra risks. The primary outcomes of interest in this study were active TB disease, completion rates, and adverse events. The meta-analysis incorporated data from 15 studies, which collectively demonstrated that the administration of a placebo resulted in a significant increase in the risk of developing TB disease by 1.279%, compared to the daily intake of isoniazid for 6 months (6H). Furthermore, treatment completion rates were significantly higher when using isoniazid plus rifapentine weekly for 3 months (3HP) and rifampicin daily for 4 months (4R), as compared to 6H. Considering adverse events, the combination of 3HP, 4R, and isoniazid administered daily for 9 months (referred to as 9H) significantly decreased adverse events by 4.53% in comparison to 6H. The risk–benefit assessment showed that alternative treatment regimens (9H, 4R, 3HR and 3HP) had a lower incidence of adverse events, while demonstrating a higher efficacy in preventing TB, as compared to 6H. This review indicates that there were no significant differences observed among various active treatment options in terms of their efficacy in preventing active TB. Moreover, completion rates were higher in 3HP and 4R, and a reduction in adverse events was observed in 3HP, 4R, and 9H.

Meropenem-vaborbactam restoration of first-line drug efficacy and comparison of meropenem-vaborbactam-moxifloxacin versus BPaL MDR-TB regimen

Meropenem in combination with β-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis (MDR-TB). The following were performed: (1) MIC experiments; (2) static time-kill studies (STKs) with different BLIs; and (3) a hollow fibre model system of TB (HFS-TB) studies with meropenem-vaborbactam combined with human equivalent daily doses of 20 mg/kg or 35 mg/kg rifampin, or moxifloxacin 400 mg, or linezolid 600 mg vs. bedaquiline-pretonamid-linezolid (BPaL) for MDR-TB. The studies were performed using Mycobacterium tuberculosis (M. tuberculosis) H37Rv and an MDR-TB clinical strain (named M. tuberculosis 16D) that underwent whole genome sequencing. Exponential decline models were used to calculate the kill rate constant (K) of different HFS-TB regimens. Whole genome sequencing revealed mutations associated with resistance to rifampin, isoniazid, and cephalosporins. The meropenem-vaborbactam MIC of M. tuberculosis was H37Rv 2mg/L and > 128 mg/L for M. tuberculosis 16D. Relebactam and vaborbactam improved both the potency and efficacy of meropenem in STKs. Meropenem-vaborbactam alone failed to kill M. tuberculosis 16D but killed below day 0 burden when combined with isoniazid and rifampin, with the moxifloxacin combination being the most effective and outranking bedaquiline and pretomanid. In the HFS-TB, meropenem-vaborbactam-moxifloxacin and BPaL had the highest K (log10 cfu/mL/day) of 0.31 (95% CI 0.17-0.58) and 0.34 (95% CI 0.21-0.56), while meropenem-vaborbactam-rifampin (35 mg/kg) had a K of 0.18 (95% CI 0.12-0.25). The K for meropenem-vaborbactam-moxifloxacin-linezolid demonstrated antagonism. Adding meropenem-vaborbactam could potentially restore the efficacy of isoniazid and rifampin against MDR-TB. The meropenem-vaborbactam-moxifloxacin backbone regimen has implications for creating a new effective MDR-TB regimen.

Can Adapalene Be Repurposed For Melanoma?

Madam, Melanoma, the most lethal skin cancer, accounts for 75% of deaths by skin cancer in the US.1 Nivolumab, Pembrolizumab, and a combination of Nivolumab and ipilimumab are used in adjuvant therapy for distant metastatic melanoma.2 The combination therapy of ipilimumab and nivolumab for melanoma per patient per month was estimated to be USD 71,689.3 Nevertheless, the efficiency of these treatments is limited.4 Furthermore, metastasis can reduce the effectiveness of cancer treatment. With time, cancer cells can also develop resistance to drugs. Hence alternative treatment regimens should be identified.5 The development of new therapies requires a vast amount of time, research, and investment. Drug repurposing provides an alternate approach to this passage. It refers to the new application of previously approved drugs. This process is rapid, potentially safer, and cost-effective.5 Continue...

Prophylactic effects of probiotic bacterium Latilactobacillus sakei on haematological parameters and cytokine profile of mice infected with Plasmodium berghei ANKA during early malaria infection

Malaria is a deadly parasitic disease caused a by protozoan parasite of the genus plasmodium. The challenges facing by chemotherapy and vector control couple with the lack of vaccine against malaria necessitate an urgent need for the development of alternative treatment regimens to combat this disease. One possible antimalarial treatment regimen is the use of probiotic bacteria as dietary supplements. Traditionally fermented milk is a rich source of probiotic bacteria that up to date, very few studies have been carried out on their immunoprotective effects against early malaria infection in mice. This study sought to assess the prophylactic activities of a probiotic bacterium Latilactobacillus sakei on malaria and inflammation in Plasmodium berghei infected mice. The probiotic bacterium was isolated from the Fulani's traditionally fermented milk and identified using the sequencing of the 16S r RNA gene. The repository activity of L. sakei on malaria was assessed using the method described by Peters with slight modification. Eighty-four BALB/c mice were randomly divided into two sets of seven groups of six mice each. One set received orally different doses of L. sakei Chloroquine and Sulfadoxine/Pyrimethamine for seven days before infection while the other set received for fourteen days before infection with 0.1 mL of 107Plasmodium berghei. Parasitaemia density, haematological parameters and inflammatory cytokines profile were evaluated. Data were presented as Mean ± SEM and analysed using SPSS version 20.0. The results of this study revealed that L. sakei significantly (p < 0.05) reduced in dose dependent manner parasite load, body weight loss and reduction of body temperature in all the treated mice when compare to untreated mice. Leukocytopenia, thrombocytosis and inflammation were also found to be significantly (p < 0.05) prevented in treated mice as compared to untreated mice.This study suggested that L sakei possesses immunomodulation and protective effects on early malaria infection in Plasmodium berghei mice.

Sirturo- a diarylquinoline (bedaquiline): a novel approach for the treatment of MDR-TB and pre-XDR TB

Sirturo (bedaquiline fumarate) is a new antitubercular class of medicine, lately, FDA, approved and indicated for use as a part of an appropriate applicable combination regimen along with other antitubercular medicines (i. e.; 2nd line anti-TB agents) for pulmonary multidrug-resistant tuberculosis (MDR TB) in grown up with age 12 years to less than 18 years of age and weighing at least 30 kg when an alternative treatment regimen cannot be considered for the reasons of resistance or tolerability. Bedaquiline, an enantiomer chemically belongs to the diarylquinoline (DAR) compound, which is nearly related to fluoroquinolones and chloroquine with differences in their side-chain moiety. Amongst all anti-TB medicines that have been approved, bedaquiline has a unique mechanism, which targets energy metabolism i. e.; adenosine triphosphate of mycobacteria, and eventually leads to bacterial cell lysis. ATP is an essential energy-producing molecule required for metabolic actions and survival of Mycobacteria and also for many other cells. Mycobacteria generally invade into well-encapsulated lung cavities and endosomes of macrophages, which can survive even under low oxygen levels leading to resistance against standard TB drugs. Bedaquiline has a spectrum of activity against drug-susceptible TB and MDR TB. Many clinical trials and studies demonstrated that bedaquiline is a crucial component of a combination regimen for multidrug-resistant TB.

Piezodynamic Eradication of Both Gram-Positive and Gram-Negative Bacteria by Using a Nanoparticle Embedded Polymeric Membrane.

Nowadays, bacterial infection is regarded as a serious threat to humankind, which needs to be taken care of. The emergence of antibiotic resistance and multidrug resistance (MDR) is rendering this situation more troublesome. However, several alternative treatment regimens have aided such diseases quite well in the recent past, among which dynamic antibacterial therapies combat this situation quite well. Among various dynamic therapies, piezodynamic therapy is a very recent avenue, in which mechanical stimuli have been exploited to treat bacterial infections. Herein, piezo-active bismuth ferrite-loaded poly(vinylidene fluoride-co-hexafluoropropylene) polymer has been utilized to eradicate gram-positive bacteria (E. faecalis) and gram-negative bacteria (E. coli). The sample has been designed in a free-standing membrane form, which, under soft ultrasound (~10 kHz), generates reactive radicals to ablate bacteria. Initially, the structure and morphology of the membrane have been substantiated by using X-ray diffraction and scanning electron microscopy methods; besides, Fourier transform infrared spectrum of the sample depicts a tremendously high value of polarizability and further confirms the piezo-activity of the membrane. More than 99% of E. coli and E. faecalis have been successfully eradicated within 30 min of ultrasound. Moreover, the solid-state structure and hydrophobic nature of the membrane help us to reuse it in a cyclic manner, which is possibly reported herein for the very first time. This novel membrane could be deployed in healthcare systems and pigment industries and could be exploited as a self-cleaning material.

Biomarkers determining treatment tactics in metastatic urothelial cancer

The implementation of innovative methods of drug therapy and biotherapy into clinical practice has significantly changed the treatment tactics for metastatic urothelial cancer. Currently, treatment regimens are successfully supplemented with immunotherapy (immune checkpoint inhibitors) or targeted therapy, and the effectiveness of such combinations can be quite high, but the optimal sequence of different types of drug therapy remains to be established. The development of correct algorithms using reliable biomarkers is necessary to select the correct sequence of prescribing drugs. Until now, the expression of programmed cell death-ligand 1 (PD-L1) and changes in fibroblast growth factor receptors 1–4 (FGFR1–4) have been the fundamental markers for choosing alternative treatment regimens for metastatic urothelial cancer. At the same time, the list of useful and sufficiently informative biomarkers is expanding, and therefore we tried to summarize the available data on the known biological markers for selection of treatment tactics for metastatic urothelial cancer.

Can mesenchymal stem/stromal cells and their secretomes combat bacterial persisters?

The increasing number of life-threatening infections caused by persister bacteria is associated with various issues, including antimicrobial resistance and biofilm formation. Infections due to persister cells are often difficult to suppress without the use of last-resort antibiotics. Throughout the world, bacterial persistence and resistance create an unmet clinical demand for the exploration of newly introduced therapeutic approaches. Mesenchymal stem / stromal cells (MSCs) have an antimicrobial activity to protect against bacterial infections, including those caused by bacterial persisters. MSCs have substantial potential to secrete antimicrobial peptides (AMPs), including cathelicidin, beta-defensins, lipocalin-2, hepcidin, indoleamine 2,3-dioxygenase (IDO), cysteine proteases, and inducible nitric oxide synthases (iNOS). MSCs possess the potential to contribute to innate immunity by regulating the immune response. Recently, MSCs and their secreted components have been reported to improve antimicrobial activity. Bactericidal activity by MSCs and their secretomes has been shown to be mediated in part by the secretion of AMPs. Even though they were discovered more than 80 years ago, therapeutic options for persisters are restricted, and there is an urgent need for alternative treatment regimens. Hence, this review intends to critically assess the current literature on the effects of MSCs and their secretomes on persister bacteria. MSCs and their secretome-based therapies could be preferred as an up-and-coming approach to reinforce the antimicrobial efficiency in persister infections.

EVALUATION OF THE EFFECTIVENESS OF NEOADJUVANT CHEMOTHERAPY IN BREAST CANCER

Relevance: Breast cancer is the most common cancer among women. Modern treatment of locally advanced breast cancer requires a multidisciplinary approach, including local treatment: surgical and radiotherapy, systemic treatment, and a wide range of medications. The importance of systemic therapy is to improve relapse-free survival based on the control of micrometastases with the potential to spread throughout the body.&#x0D; Systemic therapy for operable breast cancer includes adjuvant therapy and neoadjuvant therapy. Hormone therapy, chemotherapy, and targeted therapy represent systemic therapy, which can be prescribed individually or in combination.&#x0D; For the most effective breast cancer treatment, tumors are classified into subtypes depending on the expression of biological markers. The presence of expression of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the rate at which tumor cells divide are determined by determining the Ki67.&#x0D; It is known that neoadjuvant chemotherapy (NCT) has clinical significance in locally advanced and inoperable breast cancer. NCT increases the frequency of organ-preserving operations and the overall survival rate when a complete pathomorphological regression of the tumor (pCR) is achieved.&#x0D; The study aimed to conduct a literature review of previously published publications on the effectiveness and expediency of neoadjuvant chemotherapy for breast cancer.&#x0D; Methods: The search and analysis of scientific publications were carried out in the databases Web of Science, Pubmed, and Scopus for ten years, from 2013 to 2023. According to the search, about 3000 articles were found, and 39 sources were left during the selection according to the inclusion and exclusion criteria&#x0D; Results: Efficiency of NСT depending on different immunophenotypes in breast cancer patients was established. Tumor response was assessed according to RECIST criteria. A complete pathological response was observed more often in more aggressive subtypes of breast cancer – Her2-positive and triple-negative cancer. The relationship between pCR and long-term outcomes – OS and DFS have also been established.&#x0D; Conclusion: Neoadjuvant chemotherapy is a systemic treatment of breast cancer, the main purpose of which is to reduce the size of the tumor for the possibility of performing organ-preserving surgery, as well as to increase the overall and relapse-free survival rates. NCT allows for evaluating the effectiveness of therapy in vivo and using alternative treatment regimens without tu-mor response to the therapy.