Germ Cell Tumor of the Testis: Lethal Subtypes of a Curable Cancer.

Germ cell tumor of the testis (GCT) is a curable cancer even when it is widely metastatic; however, outcomes can differ based on tumor histology. Chemo-resistance in certain phenotypes, such as teratoma and yolk sac tumor, contributes to poor clinical outcomes in some patients with GCT. Despite this resistance to S-YSTemic therapy, many of these tumor subtypes remain amenable to surgical resection and possible cure. In this study, we report on a series of seven patients highlighting two chemo-resistant subtypes of nonseminomatous germ cell tumor (NSGCT), sarcomatoid yolk sac tumor (S-YST), and epithelioid trophoblastic tumor (ETT) for which early resection rather than additional salvage chemotherapy or high-dose intense chemotherapy might provide a superior clinical outcome and enhance cure rate.

Trichophyton indotineae, an Emerging Drug-Resistant Dermatophyte: A Review of the Treatment Options.

Background: Dermatophytosis is a prevalent superficial infection caused by filamentous fungi, primarily affecting the skin and/or its appendages. In recent years, there has been a notable increase in mycotic strains resistant to standard antifungal therapies, including Trichophyton indotineae, a dermatophyte of the Trichophyton mentagrophytes complex. This review aims to provide a comprehensive overview of the treatment options for T. indotineae, elucidating their effectiveness in managing this challenging mycotic infection. Methods: For this review, a search was conducted in the PubMed, Scopus, Web of Science, Embase, and Google Scholar databases, encompassing all published data until March 2024. English-language articles detailing therapy outcomes for patients confirmed to be affected by T. indotineae, identified through molecular analysis, were included. Results: Itraconazole was shown to be a good therapeutic choice, particularly when administered at a dosage of 200 mg/day for 1-12 weeks. Voriconazole was also demonstrated to be effective, while terbinafine exhibited a reduced response rate. Griseofulvin and fluconazole, on the other hand, were found to be ineffective. Although topical treatments were mostly ineffective when used alone, they showed promising results when used in combination with systemic therapy. Mutational status was associated with different profiles of treatment response, suggesting the need for a more tailored approach. Conclusions: When managing T. indotineae infections, it is necessary to optimize therapy to mitigate resistances and relapse. Combining in vitro antifungal susceptibility testing with mutational analysis could be a promising strategy in refining treatment selection.

Contemporary Insights into Hepatitis C Virus: A Comprehensive Review.

Hepatitis C virus (HCV) remains a significant global health challenge. Approximately 50 million people were living with chronic hepatitis C based on the World Health Organization as of 2024, contributing extensively to global morbidity and mortality. The advent and approval of several direct-acting antiviral (DAA) regimens significantly improved HCV treatment, offering potentially high rates of cure for chronic hepatitis C. However, the promising aim of eventual HCV eradication remains challenging. Key challenges include the variability in DAA access across different regions, slightly variable response rates to DAAs across diverse patient populations and HCV genotypes/subtypes, and the emergence of resistance-associated substitutions (RASs), potentially conferring resistance to DAAs. Therefore, periodic reassessment of current HCV knowledge is needed. An up-to-date review on HCV is also necessitated based on the observed shifts in HCV epidemiological trends, continuous development and approval of therapeutic strategies, and changes in public health policies. Thus, the current comprehensive review aimed to integrate the latest knowledge on the epidemiology, pathophysiology, diagnostic approaches, treatment options and preventive strategies for HCV, with a particular focus on the current challenges associated with RASs and ongoing efforts in vaccine development. This review sought to provide healthcare professionals, researchers, and policymakers with the necessary insights to address the HCV burden more effectively. We aimed to highlight the progress made in managing and preventing HCV infection and to highlight the persistent barriers challenging the prevention of HCV infection. The overarching goal was to align with global health objectives towards reducing the burden of chronic hepatitis, aiming for its eventual elimination as a public health threat by 2030.

Detection of Salmonella Reservoirs in Birds of Prey Hosted in an Italian Wildlife Centre: Molecular and Antimicrobial Resistance Characterisation.

In the European Union, salmonellosis is one of the most important zoonoses reported. Poultry meat and egg products are the most common food matrices associated with Salmonella presence. Moreover, wild and domestic animals could represent an important reservoir that could favour the direct and indirect transmission of pathogens to humans. Salmonella spp. can infect carnivorous or omnivorous wild birds that regularly ingest food and water exposed to faecal contamination. Birds kept in captivity can act as reservoirs of Salmonella spp. following ingestion of infected prey or feed. In this paper, we describe the isolation of different Salmonella serovars in several species of raptors hosted in aviaries in an Italian wildlife centre and in the raw chicken necks used as their feed but intended for human consumption. Characterisations of strains were carried out by integrating classical methods and whole genome sequencing analysis. The strains of S. bredeney isolated in poultry meat and birds belonged to the same cluster, with some of them being multidrug-resistant (MDR) and carrying the Col(pHAD28) plasmid-borne qnrB19 (fluoro)quinolone resistance gene, thus confirming the source of infection. Differently, the S. infantis found in feed and raptors were all MDR, carried a plasmid of emerging S. infantis (pESI)-like plasmid and belonged to different clusters, possibly suggesting a long-lasting infection or the presence of additional undetected sources. Due to the high risk of fuelling a reservoir of human pathogens, the control and treatment of feed for captive species are crucial.

Is Camphor the Future in Supporting Therapy for Skin Infections?

The aim of this review is to present the potential application of camphor-a bicyclic monoterpene ketone-in the prevention of skin infections. Skin diseases represent a heterogeneous group of disorders characterized by prolonged symptoms that significantly diminish the quality of life. They affect the dermis, the epidermis, and even subcutaneous tissue. They very often have a bacterial or fungal background. Therapy for dermatological skin disorders is difficult and long-term. Therefore, it is important to find a compound, preferably of natural origin, that (i) prevents the initiation of this infection and (ii) supports the skin's repair process. Based on its documented anti-inflammatory, antibacterial, antifungal, anti-acne, anesthetic, strengthening, and warming properties, camphor can be used as a preventative measure in dermatological infectious diseases and as a component in medical and cosmetic products. This work discusses the structure and physicochemical properties of camphor, its occurrence, and methods of obtaining it from natural sources as well as through chemical synthesis. The use of camphor in industrial preparations is also presented. Additionally, after a detailed review of the literature, the metabolism of camphor, its interactions with other medicinal substances, and its antimicrobial properties against bacteria and fungi involved in skin diseases are discussed with regard to their resistance.

Metabolic Reprogramming in Thyroid Cancer.

Thyroid cancer is a common endocrine malignancy with increasing incidence globally. Although most cases can be treated effectively, some cases are more aggressive and have a higher risk of mortality. Inhibiting RET and BRAF kinases has emerged as a potential therapeutic strategy for the treatment of thyroid cancer, particularly in cases of advanced or aggressive disease. However, the development of resistance mechanisms may limit the efficacy of these kinase inhibitors. Therefore, developing precise strategies to target thyroid cancer cell metabolism and overcome resistance is a critical area of research for advancing thyroid cancer treatment. In the field of cancer therapeutics, researchers have explored combinatorial strategies involving dual metabolic inhibition and metabolic inhibitors in combination with targeted therapy, chemotherapy, and immunotherapy to overcome the challenge of metabolic plasticity. This review highlights the need for new therapeutic approaches for thyroid cancer and discusses promising metabolic inhibitors targeting thyroid cancer. It also discusses the challenges posed by metabolic plasticity in the development of effective strategies for targeting cancer cell metabolism and explores the potential advantages of combined metabolic targeting.

The Rising Tide of Antibiotic Resistance: A Study on Extended-Spectrum Beta-Lactamase and Carbapenem-Resistant Escherichia coli and Klebsiella pneumoniae.

BACKGROUND: The global spread of extended-spectrum beta-lactamase (ESBL)-producing and carbapenem-resistant Enterobacterales (CRE) poses a significant concern. Acquisition of antimicrobial resistance genes leads to resistance against several antibiotics, limiting treatment options. We aimed to study ESBL-producing and CRE transmission in clinical settings. METHODS: From clinical samples, 227 ESBL-producing and CRE isolates were obtained. The isolates were cultured on bacterial media and confirmed by VITEK 2. Antibiograms were tested against several antibiotics using VITEK 2. The acquired resistance genes were identified by PCR. RESULTS: Of the 227 clinical isolates, 145 (63.8%) were Klebsiella pneumoniae and 82 (36.1%) were Escherichia coli; 76 (33.4%) isolates were detected in urine, 57 (25.1%) in pus swabs, and 53 (23.3%) in blood samples. A total of 58 (70.7%) ESBL-producing E. coli were resistant to beta-lactams, except for carbapenems, and 17.2% were amikacin-resistant; 29.2% of E. coli isolates were resistant to carbapenems. A total of 106 (73.1%) ESBL-producing K. pneumoniae were resistant to all beta-lactams, except for carbapenems, and 66.9% to ciprofloxacin; 38 (26.2%) K. pneumoniae were resistant to carbapenems. Colistin emerged as the most effective antibiotic against both bacterial types. Twelve (20.6%) E. coli isolates were positive for blaCTX-M, 11 (18.9%) for blaTEM, and 8 (33.3%) for blaNDM. Forty-six (52.3%) K. pneumoniae isolates had blaCTX-M, 27 (18.6%) blaTEM, and 26 (68.4%) blaNDM. CONCLUSION: This study found a high prevalence of drug-resistant ESBL-producing and CRE, highlighting the need for targeted antibiotic use to combat resistance.

Molecular insights to therapeutic in cancer: role of exosomes in tumor microenvironment, metastatic progression and drug resistance.

Exosomes play a pivotal part in cancer progression and metastasis by transferring various biomolecules. Recent research highlights their involvement in tumor microenvironment remodeling, mediating metastasis, tumor heterogeneity and drug resistance. The unique cargo carried by exosomes garners the interest of researchers owing to its potential as a stage-specific biomarker for early cancer detection and its role in monitoring personalized treatment. However, unanswered questions hinder a comprehensive understanding of exosomes and their cargo in this context. This review discusses recent advancements and proposes novel ideas for exploring exosomes in cancer progression, aiming to deepen our understanding and improve treatment approaches.

A Plasmodium falciparum genetic cross reveals the contributions of pfcrt and plasmepsin II/III to piperaquine drug resistance.

Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been reported, including mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and increased copies of plasmepsin II/III (pm2/3). We generated a cross between a Cambodia-derived multidrug-resistant KEL1/PLA1 lineage isolate (KH004) and a drug-susceptible Malawian parasite (Mal31). Mal31 harbors a wild-type (3D7-like) pfcrt allele and a single copy of pm2/3, while KH004 has a chloroquine-resistant (Dd2-like) pfcrt allele with an additional G367C substitution and multiple copies of pm2/3. We recovered 104 unique recombinant parasites and examined a targeted set of progeny representing all possible combinations of variants at pfcrt and pm2/3. We performed a detailed analysis of competitive fitness and a range of PPQ susceptibility phenotypes with these progenies, including PPQ survival assay, area under the dose response curve, and a limited point IC50. We find that inheritance of the KH004 pfcrt allele is required for reduced PPQ sensitivity, whereas copy number variation in pm2/3 further decreases susceptibility but does not confer resistance in the absence of additional mutations in pfcrt. A deep investigation of genotype-phenotype relationships demonstrates that progeny clones from experimental crosses can be used to understand the relative contributions of pfcrt, pm2/3, and parasite genetic background to a range of PPQ-related traits. Additionally, we find that the resistance phenotype associated with parasites inheriting the G367C substitution in pfcrt is consistent with previously validated PPQ resistance mutations in this transporter.IMPORTANCEResistance to piperaquine, used in combination with dihydroartemisinin, has emerged in Cambodia and threatens to spread to other malaria-endemic regions. Understanding the causal mutations of drug resistance and their impact on parasite fitness is critical for surveillance and intervention and can also reveal new avenues to limiting the evolution and spread of drug resistance. An experimental genetic cross is a powerful tool for pinpointing the genetic determinants of key drug resistance and fitness phenotypes and has the distinct advantage of quantifying the effects of naturally evolved genetic variation. Our study was strengthened since the full range of copies of KH004 pm2/3 was inherited among the progeny clones, allowing us to directly test the role of the pm2/3 copy number on resistance-related phenotypes in the context of a unique pfcrt allele. Our multigene model suggests an important role for both loci in the evolution of this multidrug-resistant parasite lineage.

FoxG1/BNIP3 axis promotes mitophagy and blunts cisplatin resistance in osteosarcoma.

Cisplatin (CDDP) is a commonly used chemotherapeutic for osteosarcoma (OS) patients, and drug resistance remains as a major hurdle to undermine the treatment outcome. Here, we investigated the potential involvement of FoxG1 and BNIP3 in CDDP resistance of OS cells. FoxG1 and BNIP3 expression levels were detected in the CDDP-sensitive and CDDP-resistant OS tumors and cell lines. Mitophagy was observed through transmission electron microscope analysis. The sensitivity to CDDP in OS cells upon FoxG1 overexpression was examined in cell and animal models. We found that FoxG1 and BNIP3 showed significant downregulation in the CDDP-resistant OS tumor samples and cell lines. CDDP-resistant OS tumor specimens and cells displayed impaired mitophagy. FoxG1 overexpression promoted BNIP3 expression, enhanced mitophagy in CDDP-resistant OS cells, and resensitized the resistant cells to CDDP treatment in vitro and in vivo. Our data highlighted the role of the FoxG1/BNIP3 axis in regulating mitophagy and dictating CDDP resistance in OS cells, suggesting targeting FoxG1/BNIP3-dependent mitophagy as a potential strategy to overcome CDDP resistance in OS.

Exploring Genetic Silencing: RNAi and CRISPR-Cas Potential Against Drug Resistance in Malaria.

Malaria has been one of the most lethal infectious diseases throughout history, claiming a high number of human lives. The genomic plasticity of Plasmodium falciparum, the causative agent of the most severe and deadly form of malaria, gives the parasite a constant resistance to drugs developed for its control. Despite efforts to control and even eradicate the disease, these have largely been unsuccessful due to the parasite's continuous adaptations. This study aims to examine the key genes involved in parasite resistance and propose a shift in the combat strategy. Gene silencing techniques offer promise in combating malaria, yet further research is needed to harness their potential for disease control fully. Although there is still a long way to go for the implementation of gene silencing-based therapeutic strategies, this review addresses examples of the use of such techniques in various human diseases and how they could be extrapolated for malaria treatment.

An Overview of Acridine Analogs: Pharmacological Significance and Recent Developments.

The clinical effectiveness of the available anticancer drugs has been reduced due to the development of drug resistance and serious adverse effects, which have restricted chemotherapy for cancer. Therefore, there is a persistent need for new anticancer medications with reduced side effects. Medical researchers are pursuing various methods to find new, potent, specifically targeted molecules for cancer treatment. Through various techniques, numerous molecules are discovered. However, among them, acridine stands out as a promising heterocycle that has captured the interest of medicinal chemists and acquired significant pharmacological value. The synthetic adaptability of acridine has enabled the creation of numerous derivatives with a wide range of architectural properties, further accelerating this broad spectrum of pharmacological activities. Recent studies have looked at the mechanisms by which acridine and its analogs inhibit tyrosine kinases, topoisomerases, telomerase, and DNA repair interaction. We have compiled our knowledge of acridine compounds for their anticancer activities, mechanisms of action, structure-activity relationship (SAR), and selective, specific activity against different cancer drug targets, as well as in vitro and in vivo anticancer activities of acridine and its analogs from the perspective of cancer drug discovery, in this review.

Advances in Drug Delivery Systems for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a common and catastrophic hematological neoplasm with high mortality rates. Conventional therapies, including chemotherapy, hematopoietic stem cell transplantation (HSCT), immune therapy, and targeted agents, have unsatisfactory outcomes for AML patients due to drug toxicity, off-target effects, drug resistance, drug side effects, and AML relapse and refractoriness. These intrinsic limitations of current treatments have promoted the development and application of nanomedicine for more effective and safer leukemia therapy. In this review, the classification of nanoparticles applied in AML therapy, including liposomes, polymersomes, micelles, dendrimers, and inorganic nanoparticles, is reviewed. In addition, various strategies for enhancing therapeutic targetability in nanomedicine, including the use of conjugating ligands, biomimetic-nanotechnology, and bone marrow targeting, which indicates the potential to reverse drug resistance, are discussed. The application of nanomedicine for assisting immunotherapy is also involved. Finally, the advantages and possible challenges of nanomedicine for the transition from the preclinical phase to the clinical phase are discussed.

Prevalence and transmission of pretreatment drug resistance in people living with HIV-1 in Shanghai China, 2017-2021.

The implementation of pretreatment drug-resistance (PDR) surveillance among people living with HIV-1 (PLWH) is a top priority in countries using efavirenz (EFV)/nevirapine (NVP) for first-line ART. In this study, we assessed the prevalence of PDR among PLWH in Shanghai, China during 2017-2021, and to reveal PDR transmission between Shanghai and other regions of China. A total of 5050 PLWH not on ART during 2017-2021 were included. Partial HIV-1 pol sequences were amplified, sequenced, and analysed for drug-resistance mutations (DRMs). Besides, transmission network of PDR variants was inferred using HIV-TRACE. The overall prevalence of PDR was 4.8% (242/5050; 95% CI, 4.2-5.4). Prevalence of NNRTI-associated PDR was 3.9% (95% CI, 3.4-4.5), higher than those of NRTI-associated (0.8%; 95% CI, 0.5-1.1) and PI-associated PDR (0.9%; 95% CI, 0.6-1.2). High prevalence of PDR (especially high-level resistance) to EFV (132/5050, 2.6%) and NVP (137/5050, 2.7%) were found. CRF01_AE (46.0%) was the predominant HIV-1 genotype with any DRMs, followed by CRF55_01B (21.0%), and CRF07_BC (15.1%). Two NRTI-associated (S68G/N/R and T215A/N/S/Y), five NNRTI-associated (V179D/E/T/L, K103N/R/S/T, E138A/G/K, V106M/I/A and Y181C/I) and two PI-associated mutations (M46I/L/V and Q58E) were the most common observed DRMs in PDR patients in Shanghai. The vast majority of S68G occurred in CRF01_AE (45%). M46I/L/V and Q58E showed a relatively high prevalence in CRF01_AE (4.1%) and CRF07_BC (12.6%). Transmission network analyses demonstrated cross-regional transmission links of PDR variants between Shanghai and other regions of China, which was mainly driven by the potential low-level DRM V179D/E. These results provide crucial information for clinical decision making of first-line ART in PLWH with PDR.

Personalized therapy in oncology: melanoma as a paradigm for molecular-targeted treatment approaches.

In recent decades, the field of systemic cancer treatment has seen remarkable changes due to advancements in the understanding of cancer's biology, immunology, and genetic makeup. As a result, individuals with late-stage cancers are now achieving survival rates that were previously unattainable. The goal of personalized cancer therapy is to enhance clinical outcomes by customizing drug treatments to suit the unique genetic and/or epigenetic profiles of each patient's tumor. This approach aims to reduce the side effects commonly associated with ineffective treatments. Advances in genetic sequencing and molecular cytogenetics have been instrumental in identifying cancer-driving mutations and epigenetic irregularities, leading to the development of specific molecular therapies. This review article highlights the progress and success of targeted molecular therapies in treating malignant melanoma, illustrating the concept of personalized cancer treatment.

Ciprofloxacin prophylaxis during haematopoietic cell transplantation: a role for use in patients with germ cell tumours?

Introduction. Fluoroquinolone prophylaxis during haematopoietic cell transplantation (HCT) can lead to antimicrobial resistance (AMR). Identifying the groups of patients that have the highest likelihood of benefiting from prophylactic antimicrobials is important for antimicrobial stewardship (AMS).Hypothesis. We aimed to identify groups of HCT recipients that have the highest likelihood of benefiting from prophylactic fluroquinolones.Methods. All admissions for HCT in a tertiary centre between January 2020 and December 2022 (N = 400) were retrospectively studied. Allogeneic HCT (allo-HCT) recipients had prophylaxis with ciprofloxacin during the chemotherapy-induced neutropenia, while autologous HCT (auto-HCT) recipients did not. Bacteraemias were recorded when non-contaminant bacterial pathogens were isolated in blood cultures.Results. Allo-HCT was performed for 43.3 % (173/400) of patients and auto-HCT was performed for 56.7 % (227/400). A bacteraemia was documented in 28.3 % (113/400) of cases. Allo-HCT recipients were more likely to have a Gram-positive bacteraemia (20.8%, 36/173, vs 10.1%, 23/227, P = 0.03), while a difference was not observed for Gram-negative bacteraemias (18.5%, 32/173 vs 18.1%, 41/227, P = 0.91). Among auto-HCT recipients not receiving ciprofloxacin prophylaxis, patients with germ cell tumours had the highest probability (P for trend 0.09) of recording any bacteraemia (43.5%, 10/23) followed by patients with lymphomas (32.5%, 13/40), other auto-HCT indications (22.2%, 2/9), multiple myeloma (22.1%, 29/131) and multiple sclerosis (12.5%, 3/24). The higher number of bacteraemias in patients with germ cell tumours was primarily driven by Gram-negative pathogens.Conclusions. Ciprofloxacin prophylaxis was associated with a reduced incidence of Gram-negative bacteraemias in allo-HCT recipients. Auto-HCT recipients due to germ cell tumours, not receiving ciprofloxacin prophylaxis, recorded the highest incidence of bacteraemias and represent a possible target group for this intervention.

Red light-activated depletion of drug-refractory glioblastoma stem cells and chemosensitization of an acquired-resistant mesenchymal phenotype.

Glioblastoma stem cells (GSCs) are potent tumor initiators resistant to radiochemotherapy, and this subpopulation is hypothesized to re-populate the tumor milieu due to selection following conventional therapies. Here, we show that 5-aminolevulinic acid (ALA) treatment-a pro-fluorophore used for fluorescence-guided cancer surgery-leads to elevated levels of fluorophore conversion in patient-derived GSC cultures, and subsequent red light-activation induces apoptosis in both intrinsically temozolomide chemotherapy-sensitive and -resistant GSC phenotypes. Red light irradiation of ALA-treated cultures also exhibits the ability to target mesenchymal GSCs (Mes-GSCs) with induced temozolomide resistance. Furthermore, sub-lethal light doses restore Mes-GSC sensitivity to temozolomide, abrogating GSC-acquired chemoresistance. These results suggest that ALA is not only useful for fluorescence-guided glioblastoma tumor resection, but that it also facilitates a GSC drug-resistance agnostic, red light-activated modality to mop up the surgical margins and prime subsequent chemotherapy.

Drug-Resistant Tuberculosis Case-Finding Strategies: Scoping Review.

BACKGROUND: Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic reviews assessing the effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown. OBJECTIVE: We therefore assessed the available literature on DR-TB case-finding strategies. METHODS: We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for tuberculosis (TB) symptoms, patients already diagnosed with TB, or were laboratory-based. We searched the academic databases of MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL (Cumulated Index to Nursing and Allied Health Literature), Epistemonikos, and PROSPERO (The International Prospective Register of Systematic Reviews) using no language or date restrictions. We screened titles, abstracts, and full-text articles in duplicate. Data extraction and analyses were carried out in Excel (Microsoft Corp). RESULTS: We screened 3646 titles and abstracts and 236 full-text articles. We identified 6 systematic reviews and 61 primary studies. Five reviews described the yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible tuberculosis and DR-TB contacts, and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described (1) 34 contact investigations, (2) 17 outbreak investigations, (3) 3 airline contact investigations, (4) 5 epidemiological analyses, (5) 1 public-private partnership program, and (6) an e-registry program. Primary studies were all descriptive and included cross-sectional and retrospective reviews of program data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information. CONCLUSIONS: Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardization of terminology, design, and reporting of DR-TB case-finding studies.

Molecular detection of ceftriaxone resistance in Neisseria gonorrhoeae clinical specimens: a tool for public health control.

OBJECTIVES: This study aimed to validate and implement a rapid screening assay for molecular detection of the penA-60 allele that is associated with ceftriaxone resistance in Neisseria gonorrhoeae for use on both isolate lysates and clinical specimen DNA extracts. METHODS: A N. gonorrhoeae penA real-time (RT)-PCR was adapted to include a species-specific pap confirmation target and a commercially available internal control to monitor for PCR inhibition.The modified assay was validated using N. gonorrhoeae-positive (n=24) and N. gonorrhoeae-negative (n=42) clinical specimens and isolate lysates. The panel included seven samples with resistance conferred by penA alleles targeted by the assay and four samples with different penA alleles. The feasibility of using the penA RT-PCR for molecular surveillance was assessed using clinical specimens from 54 individuals attending a London sexual health clinic who also had a N. gonorrhoeae isolate included in the 2020 Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP). RESULTS: The assay correctly identified N. gonorrhoeae specimens (n=7) with penA-60/64 alleles targeted by the assay. No penA false negatives/positives were detected, giving the penA target of the assay a sensitivity, specificity, positive and negative predicted values (PPV, NPV) of 100% (95% CIs; sensitivity; 56.1-100%, specificity; 93.6-100%, PPV; 56.1-100%, NPV; 93.6-100%).No cross-reactivity with other Neisseria species or other urogenital pathogens was detected. The N. gonorrhoeae target (pap) was detected in 73 out of 78 of the N. gonorrhoeae-positive specimens, resulting in 92.6% sensitivity (95% CI 83.0% to 97.3%), 100% specificity (95% CI 75.9% to 100%) and PPV, and a NPV of 89.4% (95% CI 52.5% to 90.9%). No penA-59/60/64 alleles were detected within the clinical specimens from the GRASP 2020 feasibility molecular surveillance study (n=54 individuals). CONCLUSION: The implementation of this PCR assay for patient management, public health and surveillance purposes enables the rapid detection of gonococcal ceftriaxone resistance conferred by the most widely circulating penA alleles.

The Role of Oxidative Metabolism in Tumorigenesis and Drug Resistance.

Aerobic glycolysis, i.e., non-oxidative glycolysis occurring under aerobic conditions (the so-called Warburg effect) is now recognized as a hallmark of cancer. However, evidence increasingly indicates that upregulated oxidative metabolism is also pivotal in tumorigenesis. In this article, we discuss factors that upregulate oxidative metabolism in tumor cells. These factors are associated with tumor cell-intrinsic and -extrinsic stimuli including antitumor drugs, requirements related to the different steps of tumorigenesis (initiation and acquisition of cancer stem-like cell functions, primary tumor growth, quiescence, metastatic dissemination), factors related to the phenotypic changes of tumor cells (e.g., autophagy and epithelial-mesenchymal transition), and particular metabolic requirements of proliferating tumor cells. In this context, we also discuss drug resistance associated with upregulated oxidative metabolism. We conclude by proposing a model whereby these factors, either individually or in combination, promote upregulation of oxidative metabolism. In the following, we address some mechanistic aspects that underlie the upregulation of oxidative metabolism and discuss the consequences on tumor prognosis. In the conclusion section of this article, we discuss possible therapeutic implications of the knowledge gathered in this field over the years.