Evaluation of proton density fat fraction (PDFF) obtained from a vendor-neutral MRI sequence and MRQuantif software.

OBJECTIVE: To validate the proton density fat fraction (PDFF) obtained by the MRQuantif software from 2D chemical shift encoded MR (CSE-MR) data in comparison with the histological steatosis data. METHODS: This study, pooling data from 3 prospective studies spread over time between January 2007 and July 2020, analyzed 445 patients who underwent 2D CSE-MR and liver biopsy. MR derived liver iron concentration (MR-LIC) and PDFF was calculated using the MRQuantif software. The histological standard steatosis score (SS) served as reference. In order to get a value more comparable to PDFF, histomorphometry fat fraction (HFF) were centrally determined for 281 patients. Spearman correlation and the Bland and Altman method were used for comparison. RESULTS: Strong correlations were found between PDFF and SS (rs = 0.84, p < 0.001) or HFF (rs = 0.87, p < 0.001). Spearman's coefficients increased to 0.88 (n = 324) and 0.94 (n = 202) when selecting only the patients without liver iron overload. The Bland and Altman analysis between PDFF and HFF found a mean bias of 5.4% ± 5.7 [95% CI 4.7, 6.1]. The mean bias was 4.7% ± 3.7 [95% CI 4.2, 5.3] and 7.1% ± 8.8 [95% CI 5.2, 9.0] for the patients without and with liver iron overload, respectively. CONCLUSION: The PDFF obtained by MRQuantif from a 2D CSE-MR sequence is highly correlated with the steatosis score and very close to the fat fraction estimated by histomorphometry. Liver iron overload reduced the performance of steatosis quantification and joint quantification is recommended. This device-independent method can be particularly useful for multicenter studies. CLINICAL RELEVANCE STATEMENT: The quantification of liver steatosis using a vendor-neutral 2D chemical-shift MR sequence, processed by MRQuantif, is well correlated to steatosis score and histomorphometric fat fraction obtained from biopsy, whatever the magnetic field and the MR device used. KEY POINTS: • The PDFF measured by MRQuantif from 2D CSE-MR sequence data is highly correlated to hepatic steatosis. • Steatosis quantification performance is reduced in case of significant hepatic iron overload. • This vendor-neutral method may allow consistent estimation of PDFF in multicenter studies.

Green roof and energy - role of climate and design elements in hot and temperate climates.

In the past few decades, the air temperature of built environment and energy demand of buildings has been increased, particularly in summer. As a consequence, the number of heat waves, heat-related mortality and morbidity have increased. The wide application of air conditioning and high level of energy use are inevitable to save people's lives, particularly in hot and temperate climates. Under these circumstances, this study offers a scoping review of the articles published between 2000 and 2020 to evaluate the role of green roofs in building energy use in hot and temperate climates. Given the ongoing trend of urban overheating, the scope of this review is limited to hot-humid, temperate and hot-dry climate zones. This scoping review shows the benefits of green roofs for reducing the demand of building energy in different climate zones and highlights the higher magnitude of energy saving in temperate climates than hot-humid or hot-dry climates provided that the green roofs are well-irrigated and uninsulated. According to the review of the articles published between 2000 and 2020, the reduction in cooling load is maximum (mean 50.2%) in temperate climate zones for well-irrigated green roofs. The effectiveness in saving cooling load reduces in hot-humid and hot-dry climate zones with means of 10% and 14.8% respectively. Green roof's design elements also strongly influence the potential in saving energy, and the effectiveness is heavily influenced by background climatic conditions. The findings of this study assist building designers and communities to better understand the amount of energy savings due to green roofs and present the results in different climates quantitatively.

Effect of post-warming culture time on the live birth rate after frozen embryo transfer.

Purpose: This study evaluated the influence of post-warming culture time on the live birth rate in day-3 and day-5 frozen embryo transfer (FET) cycles. Methods: This multicenter, retrospective cohort study was performed at IVFMD, My Duc Hospital and IVFMD Phu Nhuan, My Duc Phu Nhuan Hospital in Vietnam between October 2019 and October 2020. Women who underwent FET cycles with the transfer of ≤2 day-3 or day-5 embryos were included in the study. FET cycles were divided into four groups based on the quartiles for the time between embryo warming and embryo transfer. The primary outcome was live birth after FET. Results: Of 2548 FET cycles, 885 and 1663 cycles, respectively, had transfer of day-3 or day-5 embryos. Post-warming culture time ranged from 0.07 to 6.1 h. There were no significant differences between the post-warming culture time quartiles with respect to the number of embryos thawed, the number of embryos transferred, and the number of top-quality embryos transferred. Post-warming culture time was not significantly associated with the live birth rate in FET cycles using either day-3 or day-5 embryos. Conclusions: Post-warming culture time did not affect live birth rate in FET cycles. Therefore, IVF centers should consider scheduling workflows to best suit the patient.

Regulation of a Novel Splice Variant of Early Growth Response 4 (EGR4-S) by HER+ Signalling and HSF1 in Breast Cancer.

The zinc finger transcription factor EGR4 has previously been identified as having a critical role in the proliferation of small cell lung cancer. Here, we have identified a novel, shortened splice variant of this transcription factor (EGR4-S) that is regulated by Heat Shock Factor-1 (HSF1). Our findings demonstrate that the shortened variant (EGR4-S) is upregulated with high EGFR, HER2, and H-Rasv12-expressing breast cell lines, and its expression is inhibited in response to HER pathway inhibitors. Protein and mRNA analyses of HER2+ human breast tumours indicated the novel EGR4-S splice variant to be preferentially expressed in tumour tissue and not detectable in patient-matched normal tissue. Knockdown of EGR4-S in the HER2-amplified breast cancer cell line SKBR3 reduced cell growth, suggesting that EGR4-S supports the growth of HER2+ tumour cells. In addition to chemical inhibitors of the HER2 pathway, EGR4-S expression was also found to be suppressed by chemical stressors and the overexpression of HSF1. Under these conditions, reduced EGR4-S levels were associated with the observed lower cell growth rate, but the augmentation of properties associated with higher metastatic potential. Taken together, these findings identify EGR4-S as a potential biomarker for HER2 pathway activation in human tumours that is regulated by HSF1.

Quantum and Classical Data Transmission through Completely Depolarizing Channels in a Superposition of Cyclic Orders.

Completely depolarizing channels are often regarded as the prototype of physical processes that are useless for communication: any message that passes through them along a well-defined trajectory is completely erased. When two such channels are used in a quantum superposition of two alternative orders, they become able to transmit some amount of classical information, but still no quantum information can pass through them. Here, we show that the ability to place N completely depolarizing channels in a superposition of N alternative causal orders enables a high-fidelity heralded transmission of quantum information with error vanishing as 1/N. This phenomenon highlights a fundamental difference with the N=2 case, where completely depolarizing channels are unable to transmit quantum data, even when placed in a superposition of causal orders. The ability to place quantum channels in a superposition of orders also leads to an increase of the classical communication capacity with N, which we rigorously prove by deriving an exact single-letter expression. Our results highlight the more complex patterns of correlations arising from multiple causal orders, which are similar to the more complex patterns of entanglement arising in multipartite quantum systems.

Controlled radical polymerization of hydrophilic and zwitterionic brush-like polymers from silk fibroin surfaces.

Bombyx mori silk fibroin is a fibrous protein whose tunable properties and biocompatibility have resulted in its utility in a wide-variety of applications, including as drug delivery vehicles, wound dressings, and tissue engineering scaffolds. Control of protein and cell attachment is vital to the performance of biomaterials, but silk fibroin is mostly hydrophobic and interacts nonspecifically with cells and proteins. Silk functionalised with hydrophilic polymers reduces attachment, but the low number of reactive sites makes achieving a uniform conjugation a persistent challenge. This work presents a new approach to grow brush-like polymers from the surface of degradable silk films, where the films were enriched with hydroxyl groups, functionalised with an initiator, and finally reacted with acrylate monomers using atom transfer radical polymerisation. Two different routes to hydroxyl enrichment were investigated, one involving reaction with ethylene oxide (EO) and the other using a two-step photo-catalysed oxidation reaction. Both routes increased surface hydrophilicity, and hydrophilic monomers containing either uncharged (poly(ethylene glycol), PEG) pendant groups or zwitterionic pendant groups were polymerised from the surfaces. The initial processing of the films to induce beta sheet structures was found to impact the success of the polymerizations. Compared to the EO modified or unmodified silk surfaces, the oxidation reaction resulted in more polymer conjugation and the surfaces appear more uniform. Mesenchymal stem cell and protein attachment were the lowest on polymers grown from oxidised surfaces. PEG-containing brush-like polymers displayed lower protein attachment than surfaces conjugated with PEG using a previously reported "grafting to" method, but polymers containing zwitterionic side chains displayed both the lowest contact angles and the lowest cell and protein attachment. This finding may arise from the interactions of the zwitterionic pendant groups through their permanent dipoles and is an important finding because PEG is susceptible to oxidative damage that can reduce efficacy over time. These modified silk materials with lower cell and protein attachments are envisioned to find utility when enhanced diffusion around surfaces is required, such as in drug delivery implants.

A clinical perspective of parathyroid hormone related hypercalcaemia.

There are many causes of hypercalcaemia including hyperparathyroidism, drugs, granulomatous disorders and malignancy. Parathyroid hormone (PTH) related hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) and more rarely by familial hypocalciuric hypercalcaemia (FHH). Algorithms for diagnosis of PTH related hypercalcaemia require assessment of a 24-h urinary calcium and creatinine excretion to calculate calcium/creatinine clearance ratio and radiological investigations including ultrasound scan and 99mTc-sestamibi-SPECT/CT. To illustrate investigations and management of parathyroid-related hypercalcaemia, we present a selection of distinct cases of PHPT due to eutopic and ectopic parathyroid adenomas, as well as a case with a syndromic form of PHPT (multiple endocrine neoplasia type 1), and a case with FHH type 1 due to a CASR inactivating mutation. Additional cases with normocalcaemic hyperparathyroidism and secondary hyperparathyroidism are included for completeness of differential diagnosis. The common eutopic parathyroid adenomas are easily treated with parathyroidectomy while the less common ectopic parathyroid adenomas require more complex investigations and operative procedures such as video-assisted thoracoscopic surgery. On the other hand, the much less common FHH does not require treatment. Assessment of kin with FHH is important to identify members with this inherited condition in order to prevent unnecessary interventions.

Case of nephropulmonary fistula and literature review.

From the literature, the managements for nephropulmonary fistula were variable. We would like to present our case and review the literature for the best method of care. The common features were 1) infected kidney; 2) ipsilateral lower lobe pneumonia or pleural effusion; 3) sputum and urine culture growing the same organism. Renal gaseous content may not be present on x-ray or even CT scan. The choice of management for the nephropulmonary fistula was diverse. However, conservative managements including antibiotics, endourological procedures for stone clearance, percutaneous drainage were not successful. Nephrectomies were required. Operative tips and anaesthesia preparation recommendations are given.

A rare case of asymptomatic emphysematous pyelonephritis.

Asymptomatic emphysematous pyelonephritis is a rare but potentially life-threatening disease. Diabetes mellitus is the most recognised risk factor. Aim of this case report is to review evidence of emphysematous pyelonephritis to identify risk factors and treatment options.

Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure." METHODS: We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin. RESULTS: A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96). CONCLUSIONS: Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).

Fall in thyroid stimulating hormone (TSH) may be an early marker of ipilimumab-induced hypophysitis.

PURPOSE: Hypophysitis develops in up to 19% of melanoma patients treated with ipilimumab, a cytotoxic T-lymphocyte antigen-4 antibody. Early detection may avert life-threatening hypopituitarism. We aimed to assess the incidence of ipilimumab-induced hypophysitis (IH) at a quaternary melanoma referral centre, and to determine whether cortisol or thyroid stimulating hormone (TSH) monitoring could predict IH onset. METHODS: We performed a retrospective cohort study of ipilimumab-treated patients at a quaternary melanoma referral centre in Australia. The inclusion criteria were patients with metastatic or unresectable melanoma treated with ipilimumab monotherapy, and cortisol and TSH measurements prior to ≥ 2 infusions. The main outcomes were IH incidence and TSH and cortisol patterns in patients who did and did not develop IH. RESULTS: Of 78 ipilimumab-treated patients, 46 met the study criteria and 9/46 (20%) developed IH at a median duration of 13.0 weeks (range 7.7-18.1) following ipilimumab initiation. All patients whose TSH fell ≥ 80% compared to baseline developed IH, and, in 5/9 patients with IH, TSH fell prior to cortisol fall and IH diagnosis. Pre-cycle-4 TSH was significantly lower in those who developed IH (0.31 vs. 1.73 mIU/L, P = 0.006). TSH fall was detected at a median time of 9.2 (range 7.7-16.4) weeks after commencing ipilimumab, and a median of 3.6 (range of - 1.4 to 9.7) weeks before IH diagnosis. There was no difference in TSH between the groups before cycles 1-3 or in cortisol before cycles 1-4. CONCLUSIONS: TSH fall ≥ 80% may be an early marker of IH. Serial TSH measurement during ipilimumab therapy may be an inexpensive tool to expedite IH diagnosis.

Occurrence of 1153 organic micropollutants in the aquatic environment of Vietnam.

The rapid increase in the number and volume of chemical substances being used in modern society has been accompanied by a large number of potentially hazardous chemicals being found in environmental samples. In Vietnam, the monitoring of chemical substances is mainly limited to a small number of known pollutants in spite of rapid economic growth and urbanization, and there is an urgent need to examine a large number of chemicals to prevent impacts from expanding environmental pollution. However, it is difficult to analyze a large number of chemicals using existing methods, because they are time consuming and expensive. In the present study, we determined 1153 substances to grasp a pollution picture of microcontaminants in the aquatic environment. To achieve this objective, we have used two comprehensive analytical methods: (1) solid-phase extraction (SPE) and LC-TOF-MS analysis, and (2) SPE and GC-MS analysis. We collected 42 samples from northern (the Red River and Hanoi), central (Hue and Danang), and southern (Ho Chi Minh City and Saigon-Dongnai River) Vietnam. One hundred and sixty-five compounds were detected at least once. The compounds detected most frequently (>40 % samples) at µg/L concentrations were sterols (cholesterol, beta-sitosterol, stigmasterol, coprostanol), phthalates (bis(2-ethylhexyl) phthalate and di-n-butyl phthalate), and pharmaceutical and personal care products (caffeine, metformin). These contaminants were detected at almost the same detection frequency as in developed countries. The results reveal that surface waters in Vietnam, particularly in the center of large cities, are polluted by a large number of organic micropollutants, with households and business activities as the major sources. In addition, risk quotients (MEC/PNEC values) for nonylphenol, sulfamethoxazole, ampicillin, acetaminophen, erythromycin and clarithromycin were higher than 1, which indicates a possibility of adverse effects on aquatic ecosystems.

Patterns of antimicrobial resistance in intensive care unit patients: a study in Vietnam.

BACKGROUND: Antimicrobial resistance has emerged as a major concern in developing countries. The present study sought to define the pattern of antimicrobial resistance in ICU patients with ventilator-associated pneumonia. METHODS: Between November 2014 and September 2015, we enrolled 220 patients (average age ~ 71 yr) who were admitted to ICU in a major tertiary hospital in Ho Chi Minh City, Vietnam. Data concerning demographic characteristics and clinical history were collected from each patient. The Bauer-Kirby disk diffusion method was used to detect the antimicrobial susceptibility. RESULTS: Antimicrobial resistance was commonly found in ceftriaxone (88%), ceftazidime (80%), ciprofloxacin (77%), cefepime (75%), levofloxacin (72%). Overall, the rate of antimicrobial resistance to any drug was 93% (n = 153/164), with the majority (87%) being resistant to at least 2 drugs. The three commonly isolated microorganisms were Acinetobacter (n = 75), Klebsiella (n = 39), and Pseudomonas aeruginosa (n = 29). Acinetobacter baumannii were virtually resistant to ceftazidime, ceftriaxone, piperacilin, imipenem, meropenem, ertapenem, ciprofloxacin and levofloxacin. High rates (>70%) of ceftriaxone and ceftazidime-resistant Klebsiella were also observed. CONCLUSION: These data indicated that critically ill patients on ventilator in Vietnam were at disturbingly high risk of antimicrobial resistance. The data also imply that these Acinetobacter, Klebsiella, and Pseudomonas aeruginosa and multidrug resistance pose serious therapeutic problems in ICU patients. A concerted and systematic effort is required to rapidly identify high risk patients and to reduce the burden of antimicrobial resistance in developing countries.

Precise through-space control of an abiotic electrophilic aromatic substitution reaction.

Nature has evolved selective enzymes for the efficient biosynthesis of complex products. This exceptional ability stems from adapted enzymatic pockets, which geometrically constrain reactants and stabilize specific reactive intermediates by placing electron-donating/accepting residues nearby. Here we perform an abiotic electrophilic aromatic substitution reaction, which is directed precisely through space. Ester arms-positioned above the planes of aromatic rings-enable it to distinguish between nearly identical, neighbouring reactive positions. Quantum mechanical calculations show that, in two competing reaction pathways, both [C-H···O]-hydrogen bonding and electrophile preorganization by coordination to a carbonyl group likely play a role in controlling the reaction. These through-space-directed mechanisms are inspired by dimethylallyl tryptophan synthases, which direct biological electrophilic aromatic substitutions by preorganizing dimethylallyl cations and by stabilizing reactive intermediates with [C-H···N]-hydrogen bonding. Our results demonstrate how the third dimension above and underneath aromatic rings can be exploited to precisely control electrophilic aromatic substitutions.

Histone deacetylase activity mediates acquired resistance towards structurally diverse HSP90 inhibitors.

Heat shock protein 90 (HSP90) regulates multiple signalling pathways critical for tumour growth. As such, HSP90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may be the presence of de novo or acquired resistance within the tumours. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The resultant resistant cell lines maintained their respective levels of resistance (7-240×) in the absence of 17-AAG and were also cross-resistant with other benzoquinone ansamycin HSP90 inhibitors. Expression of members of the histone deacetylase family (HDAC 1, 5, 6) was altered in the resistant cells. To determine whether HDAC activity contributed to resistance, pan-HDAC inhibitors (TSA and LBH589) and the class II HDAC-specific inhibitor SNDX275 were found to resensitize resistant cells towards 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin. Most significantly, resistant cells were also identified as cross-resistant towards structurally distinct HSP90 inhibitors such as radicicol and the second-generation HSP90 inhibitors CCT018159, VER50589 and AUY922. HDAC inhibition also resensitized resistant cells towards these classes of HSP90 inhibitors. In conclusion, we report that prolonged 17-AAG treatment results in acquired resistance of cancer cells towards not just 17-AAG but also to a spectrum of structurally distinct HSP90 inhibitors. This acquired resistance can be inhibited using clinically relevant HDAC inhibitors. This work supports the potential benefit of using HSP90 and HDAC inhibitors in combination within the clinical setting.

Mammographically dense human breast tissue stimulates MCF10DCIS.com progression to invasive lesions and metastasis.

BACKGROUND: High mammographic density (HMD) not only confers a significantly increased risk of breast cancer (BC) but also is associated with BCs of more advanced stages. However, it is unclear whether BC progression and metastasis are stimulated by HMD. We investigated whether patient-derived HMD breast tissue could stimulate the progression of MCF10DCIS.com cells compared with patient-matched low mammographic density (LMD) tissue. METHODS: Sterile breast specimens were obtained immediately after prophylactic mastectomy from high-risk women (n = 10). HMD and LMD regions of each specimen were resected under radiological guidance. Human MCF10DCIS.com cells, a model of ductal carcinoma in situ (DCIS), were implanted into silicone biochambers in the groins of severe combined immunodeficiency mice, either alone or with matched LMD or HMD tissue (1:1), and maintained for 6 weeks. We assessed biochamber weight as a measure of primary tumour growth, histological grade of the biochamber material, circulating tumour cells and metastatic burden by luciferase and histology. All statistical tests were two-sided. RESULTS: HMD breast tissue led to increased primary tumour take, increased biochamber weight and increased proportions of high-grade DCIS and grade 3 invasive BCs compared with LMD. This correlated with an increased metastatic burden in the mice co-implanted with HMD tissue. CONCLUSIONS: Our study is the first to explore the direct effect of HMD and LMD human breast tissue on the progression and dissemination of BC cells in vivo. The results suggest that HMD status should be a consideration in decision-making for management of patients with DCIS lesions.

External nasal valve collapse: validation of novel outcome measurement tool.

BACKGROUND: We aim to validate a clinical scoring system of external nasal valve collapse. External nasal valve collapse is a rare and challenging condition. We attempted to simplify the examination of the external valve, the surgical planning and the outcome measure. To validate our external valve score, we first assessed its reliability (inter-rater agreement and test-retest repeatability). We secondly considered the clinical relevance by using our scoring system in patients undergoing septorhinoplasty for external valve collapse. METHODOLOGY: For validation, 16 Rhinologists scored patients separately on two occasions. For the clinical relevance, 26 patients with external valve collapse were scored pre- and post-operatively (responsiveness). The external valve score was correlated to peak nasal inspiratory flow. RESULTS: The devised scoring system was reliable (substantial agreement between 16 surgeons with reproducibility over time). All patients in our prospective series showed significant improvement in their external valve score. The quality of life measured by the SNOT-22 tool showed significant improvement after surgery. CONCLUSION: External nasal valve collapse can be diagnosed and graded using this simple scoring system in the outpatient clinic. This paper reinforces the pivotal role of septorhinoplasty surgery in nasal airway reconstruction and the ongoing need to quantify success.

Molecular stress-inducing compounds increase osteoclast formation in a heat shock factor 1 protein-dependent manner.

Many anticancer therapeutic agents cause bone loss, which increases the risk of fractures that severely reduce quality of life. Thus, in drug development, it is critical to identify and understand such effects. Anticancer therapeutic and HSP90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) causes bone loss by increasing osteoclast formation, but the mechanism underlying this is not understood. 17-AAG activates heat shock factor 1 (Hsf1), the master transcriptional regulator of heat shock/cell stress responses, which may be involved in this negative action of 17-AAG upon bone. Using mouse bone marrow and RAW264.7 osteoclast differentiation models we found that HSP90 inhibitors that induced a heat shock response also enhanced osteoclast formation, whereas HSP90 inhibitors that did not (including coumermycin A1 and novobiocin) did not affect osteoclast formation. Pharmacological inhibition or shRNAmir knockdown of Hsf1 in RAW264.7 cells as well as the use of Hsf1 null mouse bone marrow cells demonstrated that 17-AAG-enhanced osteoclast formation was Hsf1-dependent. Moreover, ectopic overexpression of Hsf1 enhanced 17-AAG effects upon osteoclast formation. Consistent with these findings, protein levels of the essential osteoclast transcription factor microphthalmia-associated transcription factor were increased by 17-AAG in an Hsf1-dependent manner. In addition to HSP90 inhibitors, we also identified that other agents that induced cellular stress, such as ethanol, doxorubicin, and methotrexate, also directly increased osteoclast formation, potentially in an Hsf1-dependent manner. These results, therefore, indicate that cellular stress can enhance osteoclast differentiation via Hsf1-dependent mechanisms and may significantly contribute to pathological and therapeutic related bone loss.