hTERT-Immortalized Mesenchymal Stem Cell-Derived Extracellular Vesicles: Large-Scale Manufacturing, Cargo Profiling, and Functional Effects in Retinal Epithelial Cells.

As the economic burden associated with vision loss and ocular damage continues to rise, there is a need to explore novel treatment strategies. Extracellular vesicles (EVs) are enriched with various biological cargo, and there is abundant literature supporting the reparative and immunomodulatory properties of stem cell EVs across a broad range of pathologies. However, one area that requires further attention is the reparative effects of stem cell EVs in the context of ocular damage. Additionally, most of the literature focuses on EVs isolated from primary stem cells; the use of EVs isolated from human telomerase reverse transcriptase (hTERT)-immortalized stem cells has not been thoroughly examined. Using our large-scale EV-manufacturing platform, we reproducibly manufactured EVs from hTERT-immortalized mesenchymal stem cells (MSCs) and employed various methods to characterize and profile their associated cargo. We also utilized well-established cell-based assays to compare the effects of these EVs on both healthy and damaged retinal pigment epithelial cells. To the best of our knowledge, this is the first study to establish proof of concept for reproducible, large-scale manufacturing of hTERT-immortalized MSC EVs and to investigate their potential reparative properties against damaged retinal cells. The results from our studies confirm that hTERT-immortalized MSC EVs exert reparative effects in vitro that are similar to those observed in primary MSC EVs. Therefore, hTERT-immortalized MSCs may represent a more consistent and reproducible platform than primary MSCs for generating EVs with therapeutic potential.

Purification and Molecular Docking Study on the Angiotensin I-Converting Enzyme (ACE)-Inhibitory Peptide Isolated from Hydrolysates of the Deep-Sea Mussel Gigantidas vrijenhoeki.

The objective of this study was to prepare an angiotensin I-converting enzyme (ACE)-inhibitory peptide from the hydrothermal vent mussel, Gigantidas vrijenhoeki. The G. vrijenhoeki protein was hydrolyzed by various hydrolytic enzymes. The peptic hydrolysate exhibited the highest ACE-inhibitory activity and was fractionated into four molecular weight ranges by ultrafiltration. The <1 kDa fraction exhibited the highest ACE inhibitory activity and was found to have 11 peptide sequences. Among the analyzed peptides, KLLWNGKM exhibited stronger ACE inhibitory activity and an IC50 value of 0.007 µM. To investigate the ACE-inhibitory activity of the analyzed peptides, a molecular docking study was performed. KLLWNGKM exhibited the highest binding energy (-1317.01 kcal/mol), which was mainly attributed to the formation of hydrogen bonds with the ACE active pockets, zinc-binding motif, and zinc ion. These results indicate that G. vrijenhoeki-derived peptides can serve as nutritional and pharmacological candidates for controlling blood pressure.

Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRASG12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRASG12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRASG12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).

Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.

KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients1-7. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.

The effect of shoulder muscle succinylcholine injection on the foreleg raising power: Sion's local paralysis.

Objective: We examined the change in foreleg raising power after Sion's local paralysis (SLP) with succinylcholine in the shoulder muscle. Methods: A randomized, double blind, placebo-controlled, porcine study was designed and performed at a research institution. Ten male Korean native pigs were randomized into an intervention group (n = 5) and a control group (n = 5). The injection points were in the middle of the left trapezius muscle and the middle of the left deltoid muscle. The control group received 2 ml normal saline (NS), 1 ml injected in each point. The intervention group received 0.4 mg/kg succinylcholine diluted to 2 ml in NS, and 1 ml was injected in each point. To represent the foreleg raising power, the height of the left forelegs from baseline (experiment table) was measured. We measured the foreleg height and oxygen saturation at -4, -2, 0, +2, +4, +6, +8, +10, +20, +30, and +60 min. Results: After SLP, foreleg height immediately declined in the intervention group. It recovered slightly for a few minutes and declined from 4 to 8 min. In the control group, foreleg height was relatively similar throughout the study period. A repeated-measure analysis of variance revealed a significant group × time interaction (F10,80 = 2.37, P = 0.017), a significant main effect for group (F1,8 = 6.25, P = 0.037), and a significant main effect for time (F10,80 = 4.41, P < 0.001). Post hoc analysis demonstrated that the intervention group showed significantly less foreleg raising power than the control group at 0, 4, 6, 8, 20, and 30 min (P < 0.05). Conclusions: Compared with the control group, the foreleg raising power in the intervention group immediately decreased significantly and persisted for a period after SLP, without hypoxia, in a pig model.

Feasibility study using longitudinal bioelectrical impedance analysis to evaluate body water status during fluid resuscitation in a swine sepsis model.

Fluid resuscitation is crucial in the initial management of sepsis; however, little is known about the serial changes and overall distribution of fluids administered into the body. To identify the feasibility of longitudinal bioelectrical impedance analysis during fluid treatment, a preclinical porcine model of Escherichia coli-induced sepsis was used. After sepsis induction, pigs were treated with fluid and vasopressors and monitored for up to 12 h after bacterial infusion or until death. Bipolar electrodes for bioelectrical impedance analysis were attached to the left extremities and measurements were performed every 10 min. Among the 12 subjects, 7 pigs expired during the experiment, and the median survival was 9.5 h. As sepsis progressed with an increase in cumulative fluid balance, R0 [∝ 1/extracellular water (ECW)] decreased, while Ri [∝ 1/intracellular water (ICW)] and ratio of extracellular water to total body water (ECW/TBW) increased. The phase angle constantly decreased throughout the monitoring period, and all non-survivors died when the phase angle decreased by more than 10%. Among the variables, ΔR0 and Δphase angle showed moderate negative correlations, and ΔECW/TBW showed a moderate positive correlation with the hourly fluid balance. Compared to survivors, a greater increase in ΔECW/TBW and a decrease in phase angle were observed in non-survivors over time, with an increase in cumulative fluid balance. Differences in ΔECW/TBW and phase angle emerged at 240 min when the difference in cumulative fluid balance between the two groups (survivors vs non-survivors) exceeded 1000 mL. In conclusion, continuous measurements of bioelectrical impedance analysis in a porcine sepsis model are feasible and may reflect changes in the body water profile during fluid resuscitation.

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer.

Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.

Changes in Biomarkers and Hemodynamics According to Antibiotic Susceptibility in a Model of Bacteremia.

Proper selection of susceptible antibiotics in drug-resistant bacteria is critical to treat bloodstream infection. Although biomarkers that guide antibiotic therapy have been extensively evaluated, little is known about host biomarkers targeting in vivo antibiotic susceptibility. Therefore, we aimed to evaluate the trends of hemodynamics and biomarkers in a porcine bacteremia model treated with insusceptible antibiotics compared to those in susceptible models. Extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli (E. coli, 5.0 * 10^9 CFU) was intravenously administered to 11 male pigs. One hour after bacterial infusion, pigs were assigned to two groups of antibiotics, ceftriaxone (n = 6) or ertapenem (n = 5). Pigs were monitored up to 7 h after bacterial injection with fluid and vasopressor support to maintain the mean arterial blood pressure over 65 mmHg. Blood sampling for blood culture and plasma acquisition was performed before and every predefined hour after E. coli injection. Cytokine (tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, IL-8, IL-10, C-reactive protein, procalcitonin, presepsin, heparan sulfate, syndecan, and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) levels in plasma were analyzed using enzyme-linked immunosorbent assays. Bacteremia developed after intravenous injection of E. coli, and negative conversion was confirmed only in the ertapenem group. While trends of other biomarkers failed to show differences, the trend of sTREM-1 was significantly different between the two groups (P = 0.0001, two-way repeated measures analysis of variance). Among hemodynamics and biomarkers, the sTREM-1 level at post 2 h after antibiotics administration represented a significant difference depending on susceptibility, which can be suggested as a biomarker candidate of in vivo antibiotics susceptibility. Further clinical studies are warranted for validation. IMPORTANCE Early and appropriate antibiotic treatment is a keystone in treating patients with sepsis. Despite its importance, blood culture which requires a few days remains as a pillar of diagnostic method for microorganisms and their antibiotic susceptibility. Whether changes in biomarkers and hemodynamics indicate treatment response of susceptible antibiotic compared to resistant one is not well understood to date. In this study using extended-spectrum ß-lactamase -producing E. coli bacteremia porcine model, we have demonstrated the comprehensive cardiovascular hemodynamics and trends of plasma biomarkers in sepsis and compared them between two groups with susceptible and resistant antibiotics. While other hemodynamics and biomarkers have failed to differ, we have identified that levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) significantly differed between the two groups over time. Based on the data in this study, trends of sTREM-1 obtained before the antibiotics and 2~4 h after the antibiotics could be a novel host biomarker that triggers the step-up choice of antibiotics.

Diverse alterations associated with resistance to KRAS(G12C) inhibition.

Inactive state-selective KRAS(G12C) inhibitors1-8 demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.

The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS.

Recently reported to be effective in patients with lung cancer, KRASG12C inhibitors bind to the inactive, or guanosine diphosphate (GDP)­bound, state of the oncoprotein and require guanosine triphosphate (GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRASG12C hydrolyzes sufficient GTP to allow inactive state­selective inhibition. Here, we show that RGS3, a GAP previously known for regulating G protein­coupled receptors, can also enhance the GTPase activity of mutant and wild-type KRAS proteins. Our study reveals an unexpected mechanism that inactivates KRAS and explains the vulnerability to emerging clinically effective therapeutics.

Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients.

KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing pursuit in precision oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in ∼13% of lung adenocarcinomas and, at a lower frequency, in other cancers. Preclinical studies describing their discovery and mechanism of action, coupled with emerging clinical data from patients treated with these drugs, have sparked a renewed enthusiasm in the study of KRAS and its therapeutic potential. Here, we discuss how these advances are reshaping the fundamental aspects of KRAS oncoprotein biology and the strides being made toward improving patient outcomes in the clinic.

Intrinsic ATR signaling shapes DNA end resection and suppresses toxic DNA-PKcs signaling.

Most cancer cells experience oncogene-induced replication stress and, as a result, exhibit high intrinsic activation of the ATR kinase. Although cancer cells often become more dependent on ATR for survival, the precise mechanism by which ATR signaling ensures cancer cell fitness and viability remains incompletely understood. Here, we find that intrinsic ATR signaling is crucial for the ability of cancer cells to promote DNA end resection, the first step in homology-directed DNA repair. Inhibition of ATR over multiple cell division cycles depletes the pool of pro-resection factors and prevents the engagement of RAD51 as well as RAD52 at nuclear foci, leading to toxic DNA-PKcs signaling and hypersensitivity to PARP inhibitors. The effect is markedly distinct from acute ATR inhibition, which blocks RAD51-mediated repair but not resection and engagement of RAD52. Our findings reveal a key pro-resection function for ATR and define how ATR inhibitors can be used for effective manipulation of DNA end resection capacity and DNA repair outcomes in cancer cells.

Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition.

KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma1,2. KRAS(G12C) inhibitors3,4 are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation4-6, and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.

ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells.

The ATR kinase is crucial for genome maintenance, but the mechanisms by which ATR controls the DNA repair machinery are not fully understood. Here, we find that long-term chronic inhibition of ATR signaling severely impairs the ability of cells to utilize homologous recombination (HR)-mediated DNA repair. Proteomic analysis shows that chronic ATR inhibition depletes the abundance of key HR factors, suggesting that spontaneous ATR signaling enhances the capacity of cells to use HR-mediated repair by controlling the abundance of the HR machinery. Notably, ATR controls the abundance of HR factors largely via CHK1-dependent transcription, and can also promote stabilization of specific HR proteins. Cancer cells exhibit a strong dependency on ATR signaling for maintaining elevated levels of HR factors, and we propose that increased constitutive ATR signaling caused by augmented replication stress in cancer cells drives the enhanced HR capacity observed in certain tumor types. Overall, these findings define a major pro-HR function for ATR and have important implications for therapy by providing rationale for sensitizing HR-proficient cancer cells to PARP inhibitors.

Remote detection of radioactive material using high-power pulsed electromagnetic radiation.

Remote detection of radioactive materials is impossible when the measurement location is far from the radioactive source such that the leakage of high-energy photons or electrons from the source cannot be measured. Current technologies are less effective in this respect because they only allow the detection at distances to which the high-energy photons or electrons can reach the detector. Here we demonstrate an experimental method for remote detection of radioactive materials by inducing plasma breakdown with the high-power pulsed electromagnetic waves. Measurements of the plasma formation time and its dispersion lead to enhanced detection sensitivity compared to the theoretically predicted one based only on the plasma on and off phenomena. We show that lower power of the incident electromagnetic wave is sufficient for plasma breakdown in atmospheric-pressure air and the elimination of the statistical distribution is possible in the presence of radioactive material.

Effect of the Hebei Spirit oil spill on intertidal meiofaunal communities in Taean, Korea.

In December 2007, approximately 10,900tons of oil from a crude carrier spread rapidly onto the coast of South Korea. We studied the effects of oil on meiofauna by comparing two contaminated intertidal sites with an uncontaminated site. During 2008-2009, the density of meiofauna fluctuated among the contaminated sites but did not vary by season. Seasonal changes in density were observed at contaminated sites 3years after the oil accident. Meiofauna appeared to be more sensitive to oil pollution stress at the more heavily contaminated site than at the less contaminated site. CLUSTER analysis showed that meiofauna communities in the 3years immediately following the accident significantly differed from those sampled later. A non-metric multidimensional scaling analysis showed that nematode species composition in the first month after the accident significantly differed from those sampled later. Long-term monitoring is needed to assess the effects of oil on the meiofaunal community.

Phosphoproteomics reveals distinct modes of Mec1/ATR signaling during DNA replication.

The Mec1/Tel1 kinases (human ATR/ATM) play numerous roles in the DNA replication stress response. Despite the multi-functionality of these kinases, studies of their in vivo action have mostly relied on a few well-established substrates. Here we employed a combined genetic-phosphoproteomic approach to monitor Mec1/Tel1 signaling in a systematic, unbiased, and quantitative manner. Unexpectedly, we find that Mec1 is highly active during normal DNA replication, at levels comparable or higher than Mec1's activation state induced by replication stress. This "replication-correlated" mode of Mec1 action requires the 9-1-1 clamp and the Dna2 lagging-strand factor and is distinguishable from Mec1's action in activating the downstream kinase Rad53. We propose that Mec1/ATR performs key functions during ongoing DNA synthesis that are distinct from their canonical checkpoint role during replication stress.

Liver Metastases in Prostate Carcinoma Represent a Relatively Aggressive Subtype Refractory to Hormonal Therapy and Short-Duration Response to Docetaxel Monotherapy.

BACKGROUND: We report a single institution's experience from a small series of patients suggesting that liver metastasis in metastatic castration-refractory prostate cancer (mCRPC) represents a relatively aggressive subtype that is refractory to hormonal manipulation treatment, including luteinizing hormone-releasing hormone agonist (LA) and abiraterone (Ab) therapy, although docetaxel is briefly effective. METHODS: Between 2007 and 2013, six patients with prostate cancer with liver metastases were analyzed. Biochemical response was defined as > 50% decrease in prostate-specific antigen (PSA) value. RESULTS: Two patients who presented with liver metastases died in less than 3 months after LA therapy. Two out of three patients (one died while receiving chemotherapy) received Ab after chemotherapy did not show any response and died while on therapy. One patient who presented with lung metastases initially received LA therapy and progressed on it with liver metastases in < 6 months. Thus, five of six patients did not respond to hormone therapy including LA and Ab. Three patients who received docetaxel after LA therapy had more than 50% objective PSA response with a mean survival of 4 months. CONCLUSIONS: No literature addresses the response to hormone treatment in hepatic metastasis in prostate carcinoma. This small series suggests that liver metastases in prostate carcinoma represent a relatively aggressive subset against which hormonal therapy, including the LA and Ab, appears to be ineffective. Although our patients responded to docetaxel chemotherapy, their responses were of short duration. A further clinical trial involving more patients will be necessary to substantiate our findings.

Surgery for bilateral large intracranial traumatic hematomas: evacuation in a single session.

OBJECTIVE: Management guidelines for single intracranial hematomas have been established, but the optimal management of multiple hematomas has little known. We present bilateral traumatic supratentorial hematomas that each has enough volume to be evacuated and discuss how to operate effectively it in a single anesthesia. METHODS: In total, 203 patients underwent evacuation and/or decompressive craniectomies for acute intracranial hematomas over 5 years. Among them, only eight cases (3.9%) underwent operations for bilateral intracranial hematomas in a single session. Injury mechanism, initial Glasgow Coma Scale score, types of intracranial lesions, surgical methods, and Glasgow outcome scale were evaluated. RESULTS: The most common injury mechanism was a fall (four cases). The types of intracranial lesions were epidural hematoma (EDH)/intracerebral hematoma (ICH) in five, EDH/EDH in one, EDH/subdural hematoma (SDH) in one, and ICH/SDH in one. All cases except one had an EDH. The EDH was addressed first in all cases. Then, the evacuation of the ICH was performed through a small craniotomy or burr hole. All patients except one survived. CONCLUSION: Bilateral intracranial hematomas that should be removed in a single-session operation are rare. Epidural hematomas almost always occur in these cases and should be removed first to prevent the hematoma from growing during the surgery. Then, the other hematoma, contralateral to the EDH, can be evacuated with a small craniotomy.

Cryptococcus pneumonia presenting in an immunocompetent host with pulmonary asbestosis: a case report.

INTRODUCTION: Cryptococcal infections pose a diagnostic challenge in an immunocompetent host. Asbestos exposure has been associated with pulmonary aspergillosis. This case highlights an interesting presentation of cryptococcal lung inflammation with underlying asbestosis. CASE PRESENTATION: A 63-year-old Mediterranean Caucasian woman presented with progressive dry cough of nine months duration. A computed tomography (CT) scan of her chest revealed multiple foci in the right infra-hilar region, which were seen as hot lung masses on a positron emission tomography (PET) scan. These multiple foci appeared metastatic in nature throughout both lung fields with early mediastinal invasion. A computed tomography (CT)-guided core biopsy was obtained from a dominant right lower lobe lung mass. Histology showed chronic granulomatous inflammation with numerous budding yeast forms that were GMS-, PAS-, and mucin-positive, consistent with cryptococcosis together with asbestos bodies (ferruginous). She was managed with fluconazole (400mg (6mg/kg) per day orally) daily. At her six-month follow up, she had marked improvement in her general condition along with a diminution of the lower lobe lung mass. CONCLUSION: We report a clinical and radiological improvement in a patient treated for cryptococcal pneumonia. Asbestos exposure was likely to have been an important pathophysiological precursor to infection by environmental fungi.