A Case of Lepromatous Leprosy (Lucio's Phenomenon) Presenting as Periorbital Edema.

Despite low prevalence of leprosy worldwide, new cases continue to present and require swift evaluation and diagnosis to prevent complications. Here, we describe a case of lepromatous leprosy with Lucio's phenomenon initially presenting with facial and periorbital edema. A 38-year-old Brazilian woman presented to the emergency department with facial swelling and erythema, initially treated as cellulitis. Due to rapid worsening despite broad-spectrum antibiotics, she underwent soft tissue exploration and biopsy due to concern for necrotizing fasciitis. During her course, she also developed retiform purpura of bilateral upper and lower extremities. Periorbital and lower extremity pathological specimens ultimately revealed acid-fast bacilli consistent with Mycobacterium leprae , and the patient improved with multidrug therapy. This case illustrates the diagnostic difficulty of lepromatous leprosy with Lucio's phenomenon, which can initially present with periorbital edema.

The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ.

BACKGROUND: PolyQ diseases are autosomal dominant neurodegenerative disorders caused by the expansion of CAG repeats. While of slow progression, these diseases are ultimately fatal and lack effective therapies. METHODS: A high-throughput chemical screen was conducted to identify drugs that lower the toxicity of a protein containing the first exon of Huntington's disease (HD) protein huntingtin (HTT) harbouring 94 glutamines (Htt-Q94). Candidate drugs were tested in a wide range of in vitro and in vivo models of polyQ toxicity. FINDINGS: The chemical screen identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models. Computational analyses of transcriptional signatures revealed that the effect of clofazimine was due to the stimulation of mitochondrial biogenesis by peroxisome proliferator-activated receptor gamma (PPARγ). In agreement with this, clofazimine rescued mitochondrial dysfunction triggered by Htt-Q94 expression. Importantly, clofazimine also limited polyQ toxicity in developing zebrafish and neuron-specific worm models of polyQ disease. INTERPRETATION: Our results support the potential of repurposing the antimicrobial drug clofazimine for the treatment of polyQ diseases. FUNDING: A full list of funding sources can be found in the acknowledgments section.

Microarray data analysis of antileukemic action of Cinnamoylated benzaldehyde LQB-461 in Jurkat cell line.

BACKGROUND: Leukemias stand out for being the main type of childhood cancer in the world. Current treatments have strong side effects for patients, and there is still a high rate of development of resistance to multidrug therapy. Previously, our research group developed a structure-activity study with novel synthetic molecules analogous to LQB-278, described as an essential molecule with in vitro antileukemic action. Among these analogs, LQB-461 stood out, presenting more significant antileukemic action compared to its derivative LQB-278, with cytostatic and cytotoxicity effect by apoptosis, inducing caspase-3, and increased sub-G1 phase on cell cycle analysis. METHODS AND RESULTS: Deepening the study of the mechanism of action of LQB-461 in Jurkat cells in vitro, a microarray assay was carried out, which confirmed the importance of the apoptosis pathway in the LQB-461 activity. Through real-time PCR, we validated an increased expression of CDKN1A and BAX genes, essential mediators of the apoptosis intrinsic pathway. Through the extrinsic apoptosis pathway, we found an increased expression of the Fas receptor by flow cytometry, showing the presence of a more sensitive population and another more resistant to death. Considering the importance of autophagy in cellular resistance, it was demonstrated by western blotting that LQB-461 decreased LC-3 protein expression, an autophagic marker. CONCLUSIONS: These results suggest that this synthetic molecule LQB-461 induces cell death by apoptosis in Jurkat cells through intrinsic and extrinsic pathways and inhibits autophagy, overcoming some mechanisms of cell resistance related to this process, which differentiates LQB-461 of other drugs used for the leukemia treatment.

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells.

Despite surgical treatment combined with multidrug therapy having made some progress, chemotherapy resistance is the main cause of recurrence and death of gastric cancer (GC). Gastric cancer mesenchymal stem cells (GCMSCs) have been reported to be correlated with the limited efficacy of chemotherapy in GC, but the mechanism of GCMSCs regulating GC resistance needs to be further studied. The gene set enrichment analysis (GSEA) was performed to explore the glycolysis-related pathways heterogeneity across different cell subpopulations. Glucose uptake and lactate production assays were used to evaluate the importance of B7H3 expression in GCMSCs-treated GC cells. The therapeutic efficacy of oxaliplatin (OXA) and paclitaxel (PTX) was determined using CCK-8 and colony formation assays. Signaling pathways altered by GCMSCs-CM were revealed by immunoblotting. The expression of TNF-α in GCMSCs and bone marrow mesenchymal stem cells (BMMSCs) was detected by western blot analysis and qPCR. Our results showed that the OXA and PTX resistance of GC cells were significantly enhanced in the GCMSCs-CM treated GC cells. Acquired OXA and PTX resistance was characterized by increased cell viability for OXA and PTX, the formation of cell colonies, and decreased levels of cell apoptosis, which were accompanied by reduced levels of cleaved caspase-3 and Bax expression, and increased levels of Bcl-2, HK2, MDR1, and B7H3 expression. Blocking TNF-α in GCMSCs-CM, B7H3 knockdown or the use of 2-DG, a key enzyme inhibitor of glycolysis in GC cells suppressed the OXA and PTX resistance of GC cells that had been treated with GCMSCs-CM. This study shows that GCMSCs-CM derived TNF-α could upregulate the expression of B7H3 of GC cells to promote tumor chemoresistance. Our results provide a new basis for the treatment of GC.

Novel mutations found in Mycobacterium leprae DNA repair gene nth from central India.

INTRODUCTION: The importance of DNA repair enzymes in maintaining genomic integrity is highlighted by the hypothesis that DNA damage by reactive oxygen/nitrogen species produced inside the host cell is essential for the mutagenesis process. Endonuclease III (Nth), formamidopyrimide (Fpg) and endonuclease VIII (Nei) DNA glycosylases are essential components of the bacterial base excision repair process. Mycobacterium leprae lost both fpg/nei genes during the reductive evolution event and only has the nth (ML2301) gene. This study aims to characterize the mutations in the nth gene of M. leprae strains and explore its correlation with drug-resistance. METHOD: A total of 91 M. leprae positive DNA samples extracted from skin biopsy samples of newly diagnosed leprosy patients from NSCB Hospital Jabalpur were assessed for the nth gene as well as drug resistance-associated loci of the rpoB, gyrA and folP1 genes through PCR followed by Sanger sequencing. RESULTS: Of these 91 patients, a total of two insertion frameshift mutations, two synonymous and seven nonsynonymous mutations were found in nth in seven samples. Sixteen samples were found to be resistant to ofloxacin and one was found to be dapsone resistant as per the known DRDR mutations. No mutations were found in the rpoB region. Interestingly, none of the nth mutations were identified in the drug-resistant associated samples. CONCLUSION: The in-silico structural analysis of the non-synonymous mutations in the Nth predicted five of them were to be deleterious. Our results suggest that the mutations in the nth gene may be potential markers for phylogenetic and epidemiological studies.

Challenges and advances in serological and molecular tests to aid leprosy diagnosis.

Leprosy is a neglected chronic infectious disease caused by obligate intracellular bacilli, Mycobacterium leprae and Mycobacterium lepromatosis. Despite multidrug therapy (MDT) success, leprosy accounts for more than 200,000 new cases yearly. Leprosy diagnosis remains based on the dermato-neurologic examination, but histopathology of skin biopsy and bacilloscopy of intradermal scraping are subsidiary diagnostic tests that require expertise and laboratory infrastructure. This minireview summarizes the state of the art of serologic tests to aid leprosy diagnosis, highlighting enzyme-linked immunosorbent assay (ELISA) and point-of-care tests (POCT) biotechnologies. Also, the impact of the postgenomic era on the description of new recombinantly expressed M. leprae-specific protein antigens, such as leprosy Infectious Disease Research Institute (IDRI) diagnostic (LID)-1 is summarized. Highly specific and sensitive molecular techniques to detect M. leprae DNA as the quantitative polymerase chain reaction (qPCR) and the loop-mediated isothermal amplification (LAMP) are briefly reviewed. Serology studies using phenolic glycolipid-I (PGL-I) semi-synthetic antigens, LID-1 fusion antigen, and the single fusion complex natural disaccharide-octyl (NDO)-LID show high sensitivity in multibacillary (MB) patients. However, serology is not applicable to paucibacillary patients, as they have weak humoral response and robust cell-mediated response, requiring tests for cellular biomarkers. Unlike ELISA-based tests, leprosy-specific POCT based on semi-synthetic PGL-I antigens and NDO-LID 1 antigen is easy to perform, cheaper, equipment-free, and can contribute to early diagnosis avoiding permanent incapacities and helping to interrupt M. leprae transmission. Besides its use to help diagnosis of household contacts or at-risk populations in endemic areas, potential applications of leprosy serology include monitoring MDT efficacy, identification of recent infection, especially in young children, as surrogate markers of disease progression to orient adult chemoprophylaxis and as a predictor of type 2 leprosy reactions. Advances in molecular biology techniques have reduced the complexity and execution time of qPCR confirming its utility to help diagnosis while leprosy-specific LAMP holds promise as an adjunct test to detect M. leprae DNA.

[Renal Side Effects of Novel Molecular Targeted Oncologic Agents].

The introduction of innovative therapies has changed the scenario of complications. The delay in the recognition of kidney adverse effects is partly due to the timing of the development of the kidney damage which occurs later than the observation period of registration studies, and partly to the exclusion of patients with known kidney impairment from registration trials. Renal disease has a significant impact on the management of cancer patients and often leads to discontinuation of therapy. Histological evaluations of kidney disorders induced by targeted/immunotherapy are very limited. Renal biopsy is critical for the management of renal toxicities and should be especially encouraged for patients showing adverse renal effects to novel cancer agents. We recently examined the histological features of patients treated with new cancer agents who underwent renal biopsy for new onset renal failure and/or urinary abnormalities. The cohort included 42 patients. The most frequently administered therapies were immunotherapy (54.8%) and anti-angiogenic treatments (45.2%). The most common adverse effect was tubular interstitial nephritis in the first group and thrombotic microangiopathy in the second one. Based on histological findings, definitive discontinuation of treatment could be restricted to a very limited number of patients. All of them had anti-VEGF-related TMA. Treatment discontinuation was unneeded in patients treated with ICIs. In patients treated with multidrug therapy, the histological findings made it possible to identify the weight of drug-related specific injury. Based on this data, renal biopsy should be considered in every cancer patient who develops urinary abnormalities or shows a worsening of renal function during treatment with immunotherapy or targeted therapy.

Assessment of Clinical, Histopathological, and Bacteriological Findings in Treated Leprosy Patients with Persistent Skin Lesions: A Retrospective Cohort Study.

Since the introduction of multidrug therapy (MDT), various disabilities/morbidities due to leprosy have been prevented. However, there is a subset of patients in whom the skin lesions do not resolve completely or remain unchanged despite a full course of MDT, which is a great source of anxiety to the patient and their family members. Hence, we tried to ascertain the putative causes and risk factors of persistent skin lesions (PSLs) by analyzing the clinical, histopathological, bacteriological, and drug resistance patterns. This is a retrospective, cohort study wherein 35 patients who had PSLs after completion of MDT were included. The majority of the patients were 18 to 30 years of age, with males predominating. Borderline tuberculoid leprosy was the most common clinical spectrum observed (71.4%). The majority had PSLs distributed predominantly over photo-exposed sites (upper limbs > trunk > face). Eight patients (22.8%) had a history of contact with leprosy patients in their family, and six patients (17.1%) had associated comorbidities. Improvement in histopathological parameters such as a decrease in granuloma fraction was observed in 22 patients (62.8%) with PSLs after release from treatment in comparison with baseline. Four patients (11.4%) were noted to have drug resistance (three to rifampicin and one to dapsone). Thus, our study emphasizes that leprosy patients with PSLs after completion of MDT should undergo histopathological evaluation and drug resistance studies.

Analysis of socioeconomic condition and bacillary index with respect to the development of Hansen's disease.

Background: Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae or Mycobacterium lepromatosis and mainly affects the skin and peripheral nerves. Although treatable, its early intervention can significantly reduce the occurrence of disability. India accounts for more than half of new cases globally. This study was undertaken to better understand the clinical traits of newly diagnosed cases in a tertiary facility of Western Uttar Pradesh, and a few from Madhya Pradesh and Uttarakhand. Methods: The observational prospective study was carried out on all the newly diagnosed leprosy cases who visited the Outpatient Department of ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, during October 2019-December 2022. After obtaining answers to a prestructured questionnaire with their consent, participants were enrolled in the study and underwent clinical examination and a slit-skin smear test. Results: A total of 56 cases were investigated, and among them, 20 (35.7%) and 36 (64.3%) women and men, respectively, had positive contact with persons affected by leprosy either within family, friends, or neighbors. It is observed that due to the delayed detection of leprosy cases, paucibacillary (PB) patients converted into multibacillary (MB) patients, and the number of MB cases is much higher compared to PB cases. Conclusion: Leprosy instances continue to spread frequently from sick to healthy people indicating continued transmission of leprosy in society. Multidrug therapy in the management of leprosy cases is effective; however, early diagnosis of PB cases is still a challenge and needs to be addressed on priority.

Recurrent choriocarcinoma complicated with leprosy during chemotherapy: A case report and literature review.

RATIONALE: The global prevalence of leprosy has decreased substantially, and cases of leprosy infection are extremely rare in China. In this report, we present a case of recurrent choriocarcinoma complicated by leprosy infection during chemotherapy. PATIENT CONCERNS: A 24-year-old Chinese woman (gravida 3, para 2) presented to a local hospital with vaginal bleeding. Her medical history included a previous diagnosis of hydatidiform mole. DIAGNOSES, INTERVENTIONS AND OUTCOMES: The patient was diagnosed with choriocarcinoma and received chemotherapy in 6 cycles. Shortly after the initial treatment was completed, the disease recurred twice with resistance to multiple chemotherapeutic agents. In her second recurrence of choriocarcinoma, she was diagnosed with leprosy with many cutaneous nodules throughout her entire body. The patient was administered chemical treatment for leprosy with the multidrug therapy regimen after being diagnosed. To prevent exacerbating the infection, no immunotherapy was utilized to treat cancer, and the infection was well-controlled at the conclusion of anticancer therapy. LESSONS: Because of immunological reduction, cancer patients are susceptible to a variety of infections. For patients with cancer, prevention and early detection of rare infectious diseases should receive special attention. Immunotherapy must be used with caution when treating patients with cancer and infections.

[Toxicity of targeted therapies and immunotherapy with checkpointinhibitors in Hodgkin lymphoma]. / Toxicité des thérapies ciblées et de l'immunothérapie par inhibiteurs des points de contrôle dans le lymphome de Hodgkin.

TOXICITY OF TARGETED THERAPIES AND IMMUNOTHERAPY WITH CHECKPOINT INHIBITORS IN HODGKIN LYMPHOMA. In patients at increased risk of recurrence or progression after autotransplantation, or in cases of relapse after autotransplantation or after at least two lines of treatment when intensive multidrug therapy is no longer a treatment option, targeted anti-CD30 therapy with brentuximab vedotin may be proposed. Brentuximab vedotin is a monoclonal antibody directed against CD30 and coupled with an anti-microtubule cytotoxic agent, monomethyl auristatin E (MMAE). The main adverse side effect of brentuximab vedotin is peripheral neuropathy. In patients who have relapsed after intensive chemotherapy, including autograft for patients eligible for this treatment, and after failure of brentuximab vedotin, anti-PD1 immunotherapy (nivolumab or pembrolizumab) may be offered. Anti-PD1 (Programmed cell death protein 1) side effects are immune-related, varied and unpredictable (endocrinopathies, rash, colitis, interstitial lung disease). The tolerability profiles of brentuximab vedotin and anti-PD1 and the management of the main undesirable side effects of these treatments are detailed for clinical practice.

TOXICITÉ DES THÉRAPIES CIBLÉES ET DE L'IMMUNOTHÉRAPIE PAR INHIBITEURS DES POINTS DE CONTRÔLE DANS LE LYMPHOME DE HODGKIN. Chez les patients ayant un risque accru de récidive ou de progression après une autogreffe, ou en cas de rechute après autogreffe ou après au moins deux lignes de traitement quand la polychimiothérapie intensive n'est plus une option, un traitement ciblé anti-CD30 par brentuximab vedotin peut être proposé. Le brentuximab vedotin est un anticorps monoclonal dirigé contre le CD30 et couplé à un agent cytotoxique antimicrotubule, la monométhylauristatine E. Le principal effet indésirable du brentuximab vedotin est la neuropathie périphérique. Chez les patients ayant une rechute après chimiothérapie intensive incluant une autogreffe, et après échec de brentuximab vedotin, une immuno­ thérapie anti-PD1 (nivolumab ou pembrolizumab) peut être proposée. Les effets indésirables des anti-PD1 ( programmed cell death protein 1), liés à l'immunité, sont très variés et assez imprévisibles (endocrinopathies, rash, colite, pneumopathies interstitielles). Les profils de tolérance du brentuximab vedotin et des anti-PD1 et la gestion des principaux effets indésirables de ces traitements sont détaillés pour la pratique clinique.

Open-Label Trial of Amikacin Liposome Inhalation Suspension in Mycobacterium abscessus Lung Disease.

BACKGROUND: Mycobacterium abscessus is the second most common nontuberculous mycobacterium respiratory pathogen and shows in vitro resistance to nearly all oral antimicrobials. M abscessus treatment success is low in the presence of macrolide resistance. RESEARCH QUESTION: Does treatment with amikacin liposome inhalation suspension (ALIS) improve culture conversion in patients with M abscessus pulmonary disease who are treatment naive or who have treatment-refractory disease? STUDY DESIGN AND METHODS: In an open-label protocol, patients were given ALIS (590 mg) added to background multidrug therapy for 12 months. The primary outcome was sputum culture conversion defined as three consecutive monthly sputum cultures showing negative results. The secondary end point included development of amikacin resistance. RESULTS: Of 33 patients (36 isolates) who started ALIS with a mean age of 64 years (range, 14-81 years), 24 patients (73%) were female, 10 patients (30%) had cystic fibrosis, and nine patients (27%) had cavitary disease. Three patients (9%) could not be evaluated for the microbiologic end point because of early withdrawal. All pretreatment isolates were amikacin susceptible and only six isolates (17%) were macrolide susceptible. Eleven patients (33%) were given parenteral antibiotics. Twelve patients (40%) received clofazimine with or without azithromycin as companion therapy. Fifteen patients (50%) with evaluable longitudinal microbiologic data demonstrated culture conversion, and 10 patients (67%) sustained conversion through month 12. Six of the 33 patients (18%) demonstrated mutational amikacin resistance. All were patients using clofazimine or clofazimine plus azithromycin as companion medication(s). Few serious adverse events occurred for ALIS users; however, reduction of dosing to three times weekly was common (52%). INTERPRETATION: In a cohort of patients primarily with macrolide-resistant M abscessus, one-half of the patients using ALIS showed sputum culture conversion to negative findings. The emergence of mutational amikacin resistance was not uncommon and occurred with the use of clofazimine monotherapy. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03038178; URL: www. CLINICALTRIALS: gov.

Self-reported clinical history of misdiagnosed leprosy cases in the State of Mato Grosso, Brzil, 2016-2019.

This study aimed to analyze the self-reported clinical history of patients misdiagnosed with leprosy in the State of Mato Grosso, Brazil. This is a cross-sectional study of new leprosy cases diagnosed in the State of Mato Grosso from 2016 to 2019, with individuals who were released from multidrug therapy due to misdiagnosis after starting treatment. Data were collected via telephone interviews. Over the study period, 354 leprosy cases were released from treatment due to misdiagnosis, of which 162 (45.8%) could be interviewed. All interviewees expressed dissatisfaction with their treatment, which prompted them to seek a reevaluation of their diagnosis before they were released due to "misdiagnosis". Among them, 35.8% received a final diagnosis of a musculoskeletal or connective tissue disease - mainly fibromyalgia and degenerative changes in the spine - followed by 13.6% with diagnoses of skin and subcutaneous tissue diseases. For 23.5% of the respondents, no alternative diagnosis was established, whereas 7.4% were later re-diagnosed with leprosy. Fibromyalgia and spinal problems were the most common alternative diagnoses for erroneous leprosy. Although the diagnosis of leprosy is usually clinical and does not require access to technical infrastructure in most cases, some more complex situations require diagnostic support via complementary tests, as well as close collaboration between primary care and reference services.

Leprosy in French Guiana, 2015 to 2021: Dynamics of a Persistent Public Health Problem.

A resurgence of leprosy as a public health problem in French Guiana was reported over the period 2007 to 2014, particularly among Brazilians gold miners. Prolonged multidrug therapy and reversal reactions represent a therapeutic challenge. The objective of this study was to assess the evolution of leprosy in this European overseas territory. All patients with leprosy confirmed in histopathology between 1 January 2015 and 31 December 2021 were included. A total of 86 patients were included, including 64 new cases and 22 previously diagnosed cases. Sixty patients (70%) were male, 6 cases were paediatric. Brazilian gold miners represented 44.1% of reported occupations (15/34). Maroons represented the second community (13 patients, 15%). Multibacillary and paucibacillary forms were found in 53 (71%) and 22 (29%) patients, respectively. The annual prevalence never exceeded the threshold of 1/10,000. The mean incidence and prevalence were significantly lower than during the period 2007 to 2014 (p < 0.0001). Reversal reactions were found in 29 patients and almost always required a long course of steroids. Infliximab allowed a reduction in the length of treatment with steroids in 2/2 cases. In conclusion, the prevalence of leprosy has decreased significantly in French Guiana, but remains driven by the population of illegal gold miners. Anti-tumour necrosis factor (anti-TNF) drugs represent a promising option in the management of reversal reactions.

Evolution of pediatric pharmaceutical forms for treatment of Hansen's disease (leprosy).

INTRODUCTION: Leprosy is a neglected, infectious, granulomatous and chronic disease caused by the pathological agent Mycobacterium leprae. The course of the disease is more aggressive in patients under 15 years of age, but the current treatment offered worldwide consists of solid forms, by the combination of antibiotics such as rifampicin, clofazimine and dapsone. This represents results in lack of adherence in pediatric patients and drug therapy failure, although numerous formulations and technologies have already been developed. AREA COVERED: This study aims to analyze the technological evolution of the pharmaceutical treatment of leprosy, aimed at children. A review of patents around the world was conducted to look for technical and clinical aspects of formulations and devices. EXPERT OPINION: Innovative formulations for pediatric patients were classified according to the routes of administration as oral, inhalable, injectable and transdermal. The formulations were organized as alternatives for pediatric therapy, taking into account the physicochemical aspects of drugs and the physiological aspects of pediatric patients. Among the difficulties for the patented formulations to reach the market, of special note is the low stability of the physicochemical characteristics of the drugs. Optimization of formulations would favor the pediatric treatment of leprosy, aiming at therapeutic success.

Frontiers of cardiovascular polypills: From atherosclerosis and beyond.

Fixed-dose combination (FDC) therapies (also known as polypills) remain underutilized in clinical practice despite over two decades of evidence from randomized controlled trials demonstrating increased adherence to multidrug therapy, improved cardiovascular disease (CVD) risk factor control, and lower incidence of cardiovascular events. Evidence demonstrates that FDC-based implementation strategies can substantially complement and augment current strategies for CVD risk prevention globally. The next decade is likely to extend the frontier of cardiovascular FDC therapies, particularly given expected advances in FDC manufacturing technology and accessibility. FDC-based anti-hypertensive therapies are emerging as integral components of a pragmatic blood pressure lowering strategy. Cardiovascular FDCs are rapidly approaching its coming of age, transforming from heavily hyped research tools to pragmatic clinical instruments. This review evaluates the current evidence for cardiovascular FDCs, barriers to current use, and potential next generation advances.

N-2-Hydroxypropylmethacrylamide-Polycaprolactone Polymeric Micelles in Co-delivery of Proteasome Inhibitor and Polyphenol: Exploration of Synergism or Antagonism.

Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL (N-2-hydroxypropylmethacrylamide-polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA-HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ-HP-PCL PMCs, while CFA-HP-PCL PMCs significantly (p < 0.001) scavenged the ROS generated in 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ-HP-PCL PMCs (p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ-HP-PCL PMCs than BTZ+CFA-HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs (p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.

Rational pemetrexed combined with CIK therapy plus anti-PD-1 mAbs administration sequence will effectively promote the efficacy of CIK therapy in non-small cell lung cancer.

Cytokine-induced killer (CIK) cells are heterogeneous cells composed mainly of CD3+CD56+ T cells. As an important treatment method of adoptive therapy, it has shown promising efficacy in many clinical trials, especially in combination with multidrug therapy. However, the maximal antitumor efficacy of CIK therapy in the combined administration of multidrug and CIK therapies and which administration scheme can maximize the antitumor efficacy of CIK therapy are still remain unclear. In this study, we observed that pemetrexed administration prior to the injection of CIK cells maximizes the efficacy of CIK therapy. Anti-PD-1 mAbs should be administered prior to CIK cell injection to maximize the efficacy of the therapy. However, administering anti-PD-1 mAbs after CIK cell injection significantly affects the binding rate of anti-PD-1 mAbs to the PD-1 receptor on CIK cells, affecting the efficacy of the antitumor therapy. In conclusion, our study observed that a rational administration sequence of pemetrexed combined with CIK therapy and anti-PD-1 mAbs significantly promotes the efficacy of CIK therapy, providing an experimental basis for the combination therapy mode and regimen of CIK therapy in clinical practice. We hope that this study can provide patients with lung adenocarcinoma with a prolonged survival time.

Nontuberculous Mycobacterial Infections in Cystic Fibrosis.

Nontuberculous mycobacteria (NTM) are important pathogens, with a longitudinal prevalence of up to 20% within the cystic fibrosis (CF) population. Diagnosis of NTM pulmonary disease in people with CF (pwCF) is challenging, as a majority have NTM infection that is transient or indolent, without evidence of clinical consequence. In addition, the radiographic and clinical manifestations of chronic coinfections with typical CF pathogens can overlap those of NTM, making diagnosis difficult. Comprehensive care of pwCF must be optimized to assess the true clinical impact of NTM and to improve response to treatment. Treatment requires prolonged, multidrug therapy that varies depending on NTM species, resistance pattern, and extent of disease. With a widespread use of highly effective modulator therapy (HEMT), clinical signs and symptoms of NTM disease may be less apparent, and sensitivity of sputum cultures further reduced. The development of a disease-specific approach to the diagnosis and treatment of NTM infection in pwCF is a research priority, as a lifelong strategy is needed for this high-risk population.

Lucio phenomenon with concomitant necrotizing fasciitis and acute kidney injury.

Lucio phenomenon is a rare vasculopathy that can occur in patients with Hansen disease, particularly diffuse lepromatous leprosy. It is characterized by retiform purpura and necrotic ulcerations, most commonly affecting the extremities. Diagnosing Lucio phenomenon can be challenging, especially when secondary bacterial infections occur. We report a patient with Lucio phenomenon who presented with acute necrotizing fasciitis of his left upper extremity and a 10-year history of chronic ulcerations. Shortly following admission, he also developed acute kidney injury. The necrotizing fasciitis was treated with prompt surgical debridement and intravenous antibiotics. Biopsy and PCR of a right upper extremity ulcer confirmed the presence of Mycobacterium lepromatosis. Multidrug therapy and prednisone were used to treat the Lucio phenomenon. After initiating treatment, no new lesions developed, kidney function improved, and the patient underwent successful skin graft of his left upper extremity. Although corticosteroid use is controversial, our patient's marked response to multidrug therapy with prednisone highlights the importance of this regimen in severe presentations of Lucio phenomenon. To the best of our knowledge, only two other cases of Lucio phenomenon confirmed to be caused by M. lepromatosis have been reported in living patients (rather than retrospectively identified post-mortem), underscoring the importance of the presented clinical course and treatment regimen.